Journal Pre-proof

Large treatment effect with extended home-based transcranial direct

current stimulation over dorsolateral prefrontal cortex in fibromyalgia:
A Proof of Concept Sham-Randomized Clinical Study

Aline P Brietzke , Maxciel Zortea , Fabiana Carvalho ,

Paulo R S Sanches , Jr Danton P Silva ,
Iraci Lucena da Silva Torres , Felipe Fregni , Wolnei Caumo

PII: S1526-5900(19)30770-9
DOI: https://doi.org/10.1016/j.jpain.2019.06.013
Reference: YJPAI 3770

To appear in: Journal of Pain

Received date: 17 February 2019

Revised date: 23 May 2019
Accepted date: 27 June 2019

Please cite this article as: Aline P Brietzke , Maxciel Zortea , Fabiana Carvalho ,
Paulo R S Sanches , Jr Danton P Silva , Iraci Lucena da Silva Torres , Felipe Fregni ,
Wolnei Caumo , Large treatment effect with extended home-based transcranial direct current
stimulation over dorsolateral prefrontal cortex in fibromyalgia: A Proof of Concept Sham-Randomized
Clinical Study, Journal of Pain (2019), doi: https://doi.org/10.1016/j.jpain.2019.06.013

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Highlights

 An extended period of self-applied tDCS at home produced improvement in

fibromyalgia pain

 Findings support the feasibility of home-based tDCS to o improve fibromyalgia

symptoms

 The results provide additional data to use the DLPFC as a target for the
treatment of fibromyalgia

 The serum BDNF may be a valuable predictor of the magnitude of tDCS on

pain scores decreases
Large treatment effect with extended home-based transcranial direct current stimulation

over dorsolateral prefrontal cortex in fibromyalgia: A Proof of Concept Sham-

Randomized Clinical Study.

Aline P Brietzke1,2, Maxciel Zortea1,2, Fabiana Carvalho1,2, Paulo R S Sanches3, Danton P Silva

Jr3, Iraci Lucena da Silva Torres, Felipe Fregni4, Wolnei Caumo1,2,4,5,6

1
Post-Graduate Program in Medical Sciences, School of Medicine, Universidade Federal do
Rio Grande do Sul (UFRGS); 2Laboratory of Pain and Neuromodulation at Hospital de
Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil; 3Laboratory of Biomedical Engineer at
HCPA; 4Laboratory of Neuromodulation and Center for Clinical Research Learning, Physics
and Rehabilitation Department, Spaulding Rehabilitation Hospital, Boston, MA, USA; 5Pain
and Palliative Care Service at HCPA and 6Department of Surgery, School of Medicine,
UFRGS.

CORRESPONDING AUTHOR: Wolnei Caumo MD, PhD; Department: Laboratory of Pain

and Neuromodulation; Institution: Hospital de Clínicas de Porto Alegre at UFRGS. Address:
Ramiro Barcelos, 2350 - CEP 90035-003 Bairro Rio Branco - Porto Alegre – RS. Phone: (55)
51- 3359.8083. Fax: (55) 51- 3359.8083

EMAIL ADDRESSES OF CO-AUTHORS:

Aline Patrícia Brietzke ([email protected])

Maxciel Zortea ([email protected])
Fabiana Carvalho ([email protected])
Assunta Gasparin ([email protected])
Paulo Roberto Stefani Sanches ([email protected])
Danton Pereira da Silva Jr ([email protected])
Wolnei Caumo ([email protected])
Disclosures section

The present research was supported by the following Brazilian funding agencies: (i)

Committee for the Development of Higher Education Personnel—CAPES PNPD (grant to MZ

with Post doctorate scholarship, Grant #2015; AB, FC). (ii) National Council for Scientific and

Technological Development - CNPq (grant to Dr. WC). (iii) Post graduate Program in Medical

Sciences of Medical School of the Federal University of Rio Grande do Sul. (iv) Post graduate

Research Group at the Hospital de Clínicas de Porto Alegre (AS, PS, DS). (v) Foundation for

Support of Research at Rio Grande do Sul (FAPERGS). Brazilian Innovation Agency (FINEP

[Financiadora de Estudos e Projetos]); process number 1245/13 to Iraci LS Torres and Wolnei

Caumo). Grant (FAPERGS-PRONEM: no 16/2551-0000249-5). WC, FF agreement to be

accountable for all aspects of the work in ensuring that questions related to the accuracy or

integrity of any part of the work are appropriately investigated and resolved.
Abstract

This randomized, double-blind controlled trial tested the hypothesis that sixty sessions

of home-based anodal (a)-transcranial direct current stimulation (tDCS) over dorsolateral

prefrontal cortex (DLPFC) would be better than home-based sham-tDCS to improve the

widespread pain and the disability-related to pain (DRP). tDCS was self-administered with a

specially developed device after in-person training. The anodal-tDCS (2mA for 30 mins) over

the left DLPFC was self-administered with a specially developed device following in-person

training. Twenty women, 18–65 years-old were randomized into two groups [active-(a)-tDCS

(n=10) or sham-(s)-tDCS (n=10)]. Post hoc analysis revealed that after the first 20 sessions of

a-tDCS the cumulative pain scores reduced by 45.65% [7.25 (1.43) vs. 3.94 (1.14), active vs.

sham tDCS, respectively]. After 60 sessions, during the 12-week assessment, pain scores

reduced by 62.06% in the actively group [VAS reduction, 7.25 (1.43) to 2.75 (0.85)] compared

to 24.92% in the s-tDCS group, [mean (SD) 7.10 (1.81) vs. 5.33 (0.90)], respectively. It

reduced the risk for analgesic use in 55%. Higher serum levels of the brain-derived-

neurotrophic factor (BDNF) predicted higher decreases on the pain scores across of treatment.

PERSPECTIVE: These findings bring three important insights: (i) show that an extended period

of treatment (60 sessions, to date the largest number of tDCS sessions tested) for fibromyalgia

induces large pain decreases (a large effect size of 1.59) and (ii) support the feasibility of

home-based tDCS as a method of intervention; (iii) provide additional data on DLPFC target

for the treatment of fibromyalgia. Finally, our findings also highlight that BDNF to index

neuroplasticity may be a valuable predictor of the magnitude of pain scores decreases across

the treatment.

Keywords: Fibromyalgia, pain, tDCS, disability, depression, BDNF.

Trial registration: number NCT02652988.

Introduction

Fibromyalgia encompasses symptoms of central sensitization syndrome (CSS)26 such as

increased levels of emotional distress, sleep disorders, depressed mood, catastrophizing

thinking, cognitive deficits, and memory impairment58 However, according to systematic

reviews, the pharmacologic treatments have a limited role in a substantial number of

fibromyalgia patients.22,23 A new option with growing evidence for fibromyalgia treatment is

the transcranial direct current stimulation (tDCS). Its effect is likely sensible to the neuroplastic

state, as demonstrated in recent studies in the fibromyalgia serum brain-derived neurotropic

factor (BDNF) predicted the tDCS effect on the short-term memory42 and improvement the

disability due to pain after hallux valgus surgery.41

The primary motor cortex (M1) has been the most studied target in order to improve the
24,31,59
pain However, a short-term applications of the anodal tDCS over the left dorsolateral

prefrontal (DLPCF) cortex improved the fatigue,11 the pain and the cognitive performance in

fibromyalgia.11,42,46 In the same way, the tDCS efficacy for depression on DLPFC has been
5,30
consistently demonstrated Improvement in the pain scores was in favor of tDCS applied

over M1 with a number of five to ten sessions of 20 min tDCS sessions of 2 mA.18,50,59

However, with ten sessions, the benefits were maintained for 60 days after treatment ended.50

The same study showed that ten tDCS sessions over DLPFC did lead to a transient

improvement in pain scores 14,50 and quality of life.50 Another study found that eight sessions of

tDCS applied over the DLPFC (20 min tDCS sessions of 1.5 mA) spread over 4 weeks was

enough to reduce pain symptoms in fibromyalgia.49 In the same way, the efficacy of tDCS over

the DLPFC in depression has been demonstrated.5,30 Taking into account that in chronic pain

alterations in the anatomical integrity and functioning of brain regions involved in both pain

control and cognitive and/or emotional functioning6 the DLPFC is an appropriate site to apply

tDCS aiming to improve pain and other cardinal symptoms of fibromyalgia (i.e., sleep quality,
depressive symptoms, and the disability due to pain). In addition, the use of this montage is

supported by the well-established relationship between depression and chronic pain.18,34

As aforementioned, the evidence about the tDCS efficacy on fibromyalgia is growing.

However, at present usually the treatments using tDCS are done under direct supervision in

medical centers and in addition current data has shown that prolonged treatments with up to 30

sessions may be needed for treatment efficacy.12 Thus, to make it feasible to offer a device to

use at home, our group recently published the results of the validation of the tDCS device

developed by our group.7 They showed that the method is safe with effects like observed in

studies that the stimulation was administered in medical centers. This home-based (HB-)-tDCS

device allows programming the parameters of the stimulus according to predefined by the

clinician with a lock system to avoid changes by other subjects. In addition, it allows

monitoring the adherence to treatment by recording the time of use, impedance, and current

flow. Thus, this study tested the hypothesis that sixty sessions during 12 weeks of (HB-)-

active-(a)DCS on the left anodal DLPFC and the right cathodal DLPFC would be better than

sham-tDCS to improve the daily pain scores across twelve weeks of treatment (primary

outcome). Additionally, we examined the impact of the cumulative effect of tDCS on pain

following the 20th and 60th session. Also, we investigated whether the neuroplasticity state,

as assessed by the serum BDNF at baseline could predict the tDCS effect on pain. Secondary

outcomes were other measures, namely disability due to pain, analgesic use, psychological

symptoms (depressive symptoms, catastrophizing) and pain threshold.

Materials and methods

Study design and eligibility

The Research Ethics Committee approved the protocol at the Hospital de Clínicas de Porto

Alegre (HCPA). Institutional Review Board IRB (CAAE 35753214.4.0000.5327). Patients

provided oral and written informed consent before participating in this randomized, double-
blind, sham-controlled trial. De-identified data relating to intervention and primary outcomes

will be made available on request to Caumo W([email protected]) with no time restriction.

Recruitment was undertaken in the time from January 2017 to july 2018.

Inclusion and exclusion criteria

We included 20 adult females, right-handed, aged 18 to 65 years, who read and write.

They were recruited from outpatients’ pain clinic of the HCPA and via newspaper publicity.

They were included if had a diagnosis for fibromyalgia by standard assessment protocol criteria

for Diagnosis of fibromyalgia (according to ―American College of Rheumatology - 2016

Revisions to the 2010/2011) applied by physicians with more than ten years of experience in

pain care. They should present daily disability for the routine activities due to

fibromyalgiaduring the three months preceding the enrolment, report a score of at least 50 mm

on the 0-100 mm visual analog scale (VAS 0-100mm). Also, they had agreed that could not

change doses of antidepressant and anticonvulsants drugs during the study period. Exclusion

criteria: to have contra-indications for NIBS according to recommended by Guideline;38 to

have a positive history of rheumatoid arthritis, lupus, autoimmune disease, neurologic or

oncologic disease and any clinical disease uncompensated (i.e., ischemic heart disease, renal

disease, hepatic disease, etc.). Also, were excluded if had used illicit drugs in the last six

months.

Sample size justification

We estimated a sample size based on pain scores of our previous study (these data

relating to pain measures were not publish).51 To detect 2.5-cm between-group difference in

pain scores on the VAS at 12 weeks of treatment and a standard deviation of 1 (assuming a

power of 0.80, two-sided, significance level of 0.05, 0.6 correlation among repeated measures

and a losses of 10% across the study) the analysis indicated a sample size of 16 subjects,
divided into two balanced groups (n=8) with a ratio 1:1. Taking into account the multiple

outcomes, the final sample size was 20 patients (10 per group). This difference permits to

detect a moderate effect size (f=0.2).

Randomization

Randomized numbers were generated using appropriate software to assign 20 patients,

an allocation of 1:1 the a-tDCS or s-tDCS groups. To avoid that evaluators were predicting

what the next patients would be allocated for treatment, we used four blocks of five. Before the

recruitment phase, two investigators who made the randomization and they were not involved

in the patient’s assessments prepared the envelopes which contained the number of

randomization. Envelops were sealed, numbered sequentially and after the participant

consented to participate in the trial; they were opened in the numerical order registered in the

outside of the envelope.

Blinding

During the entire protocol timeline participants, research staff, and investigators were

all blinded to allocation. Two biomedical engineers (PRS and DPS) who were not involved in

the patients` assessment prepared the tDCS device to provide active stimulation or sham

according to randomization code. To ensure patient’s blinding, in sham stimulation the

equipment was pre-programmed to deliver a 15 seconds ramp-up (0 to 2 mA) stimulation, then

a 15s ramp-down stimulation until the current intensity was switched off. At the experiment

end, we asked participants if they received active or sham therapy and they rated their

confidence in the treatment received on a Likert scale from 1 (no confidence) to 5 (entirely

confident).

Intervention
 The anodal electrode was used over the left DLPFC and the cathode electrode at right

DLPFC. The current applied was of the 2mA for 30 minutes for five consecutive days for 12

weeks.11,38,39 Current was delivered using 35cm2 electrodes coated with a vegetable sponge,

which was moistened with saline solution before the start of the stimulation by two silicone

cannulas coupled to the electrode. A medical engineer prepared the device to offer a fixed

number of simulations, with a minimum interval between two consecutive sessions of 16 hours.

Neoprene caps were produced in small, medium and large sizes and cap size was selected

according to the circumference of each patient's head. By doing that and given that the position

of the electrode inside the cap was fixes, the electrode position was then accurate for the

subjects To facilitate the identification and avoid wrong placement of the electrodes, the anode

was painted red and cathode black, although the whole equipment (device and cap) was handed

to the participant already set up and they cannot change any part it. Details of the device and

the step-by-step process to self-administration the tDCS-device to be used at home can be seen

clicking in the link <https://www.jove.com/video/57614/home-based-transcranial-direct-

current-stimulation-device-development>. Patients came to the center for the baseline

assessment (visit 1), after six weeks of treatment (visit 2) and after the end of the treatment

(visit 3). At visit 2 and 3, we verified the compliance of treatment stored in the device system.

This information was downloaded by an engineer not involved in the patients' treatment. These

records allowed us to see the parameters such as mean current intensity, impedance, duration of

the session and the time of application. The engineer maintained these data under his care until

the end of the study. Details about the depiction of the study procedures over time are

presented in Figure 1.

------------------------ Insert Figure 1-----------------------------

Instruments and Assessments

 The primary outcomes were the pain score on the Visual Analog Scale (VAS) [global

pain in the last 24 hours]. The secondary outcomes were the disability related to pain (DRP) as

measured by the Brazilian Portuguese version of the Profile of Chronic Pain: Screen (B-

PCP:S),9 analgesic use, psychological symptoms (depressive symptoms, catastrophizing), sleep

quality and psychophysical measures [pain pressure threshold (PPT) and heat pain threshold

(HPT)]).

Primary outcome – global pain in the last 24 hours across 12 weeks of treatment

a) The pain intensity was assessed with a 100-mm VAS. The VAS scores ranged from no pain

(zero) to worst possible pain (100 mm). They were asked to answer the following question

using the pain VAS: i) considering your pain, how intense was your worst pain during the last

24 hours.

Secondary outcomes- disability due to pain, analgesic use and psychophysical measurements

b) B-PCP:S - Brazilian Portuguese version of the Profile of Chronic Pain: Screen - was used to

identify an individual’s multidimensional pain experience. The B-PCP:S subscales assess the

severity (four items; possible range 0–32), interference in daily life (six items; possible range

0–36), and emotional burden (five items; possible range 0–25). An accepted criterion to define

disability related to pain is a chronic or recurrent pain or discomfort causing restriction, 9,53

thus we assumed that higher scores on the B-PCP:S indicated higher disability or dysfunction

at work, at home, during social situations and/or a higher emotional burden.

c) Supplementary analgesia use: patients could use additional analgesic medication

(acetaminophen, ibuprofen, codeine or tramadol) to relieve their pain if necessary. They were

allowed to use as a rescue analgesia 750 mg of acetaminophen up to four times per day (QID)

and 200 mg of ibuprofen at maximum QID. Also, If their pain persisted, they could use

Dorflex® (Sanofi Aventis, São Paulo, Brazil; 35 mg of orphenadrine citrate combined with
 300 mg of dypirone and 50 mg of caffeine). If the pain persisted, patients could use 60 mg of

codeine up to QID or tramadol three times per day (TID). All medications could be used a

maximum of four times a day. The patients were asked to record their analgesic intake during

the treatment period in their diaries, and these diaries were reviewed at each visit to the center.

The total analgesic dose taken during the last week of treatment was considered for the

analysis.

d) Quantitative sensory testing: a standardized protocol of quantitative sensory testing (QST)

was performed by the same researcher. The measure applies the method limits with a

computer Peltier-based device thermode (30X30mm)44 attached to the skin on the ventral

aspect of the mid-forearm. The set at 32oC and was increased at a rate of 1oC/s to a maximum

of 52oC. The heat pain threshold of each patient was defined as the means of three

assessments performed with an inter-stimulus interval of 40 s.44

e) PPT: was performed in the right arm using an electronic algometer (J-Tech Medical

Industries, Midvale, UT, USA). Patients were instructed to alert when experiencing pain onset

verbally. The PPT was defined as mean of three successive measurements carry-out at 3–5-

minute intervals.3

Clinical measurements: depressive symptoms, pain catastrophizing and sleep quality

All of the psychological tests used in this study have been validated for the Brazilian
9,45,56
population The following instruments were used to assess psychological symptoms and

sleep quality: The Beck Depression Inventory-II (score range from 0- 63),56 the Brazilian Pain

catastrophizing Scale – BP-PCS (scores range from 0 – 52)45 and the Pittsburgh Sleep Quality

Index (PSQI) (score range from 0-21).2

Other Instruments and Assessments

 To evaluate the quality of life was used the Fibromyalgia Impact Questionnaire (FIQ).

To assess anxiety was used the State-Trait Anxiety Inventory (STAI).27 Central Sensitization

Inventory, modified and validated for a Brazilian population (CSI-BP) was used to assess

symptoms of central sensitization syndrome.8 Demographic data and medical comorbidities

were evaluated using a standardized questionnaire. To assess side effects of tDCS was used the

Systematic Assessment for Treatment questionnaire.

f) BDNF serum levels: Baseline blood samples were collected and after the 60th session in the

end of treatment. At the maximum time of one hour after collection, the blood samples were

centrifuged, and the serum separated in 0.5 ml aliquots for further analysis. The BDNF

serum levels were determined by sandwich ELISA using monoclonal antibodies specific for

the neurotrophin (R&D Systems, Minneapolis, United States) using manufacturer’s

protocol. All samples were assayed in duplicate in order to avoid intra-assay variation. Two

plates per kit were used over two different days, within the same week, in order to assess the

inter-assay variation. Protocols were performed according to the manufacturer’s instructions.

The Enzyme-linked Immunosorbent determined serum BDNF. The lower detection limit for

BDNF of the kit is 7.8 pg/ml. Assay (ELISA) using a ChemiKine BDNF Sandwich ELISA kit,

CYT306 (Chemicon/Millipore, Billerica, MA, USA). Optical density was measured using an

ELISA reader at wavelength of 450 nm (GloMax®-Multi Microplate Reader, Promega) or the

Bio-Plex®-200 instrument (Bio-Rad) for the multiplexing assay measurements. Total protein

was measured by the Bradford method using bovine serum albumin as the standard. The data

were expressed in pg/mg of protein.

Statistical Analysis

The t-test for independent samples, chi-square or Fisher’s exact tests were used to

compare continuous and categorical variables, respectively. For non-parametric distributions,

group comparisons were performed using the Wilcoxon-Mann-Whitney test. Continuous

variables were tested for normal distribution using Shapiro-Wilk normality test.

Treatment effects were estimated through a Mixed Model for Repeated Measurements

(MMRM), assuming an unstructured correlation matrix52. The BDNF of baseline was used to

examine the influence of neuroplasticity state as a modulator of the treatment effectiveness in

the daily pain scores reported in the VAS across 12 weeks of treatment. The models included

fixed effects for treatment group (a-tDCS or s-tDCS) was used to analyze the main effect on

the primary outcome [cumulative of daily score change on the VAS (0–10) for each week

throughout the treatment time (12 weeks) and secondary outcome B-PCP:S and its subscales

assessed after 30th sessions (6 week) and after treatment end (12th week)]. The subject

identification was used to test the interaction between treatment group and time. The main

effect of the predicted marginal mean differences between interventions was calculated by

pairwise comparisons with an adjustment to account for multiple comparisons by the

Bonferroni’s Test. Missing values were not a significant problem in the analysis of the data set,

because we lost fifty daily assessments in a total of 1200 daily pain report in the VAS (4.16%).

A multivariate analysis of covariance (MANCOVA) was used to analyze the treatment

effect (factor) on the mean variation for delta [(Δ)-values, post-intervention minus pre-

intervention] of secondary outcomes: HPT, HPTo, depressive symptoms, pain catastrophizing

and sleep quality, included in the model as dependent variables. Effect size (ES) was computed

by the standardized difference mean (SDM) (Mean difference a-tDCS vs. s-tDCS)/pool of

baseline standard deviation (SD)]. The ES was interpreted as follows: small if lower than 0.20

to 0.49; moderate if between 0.50–0.79; and large if larger than 0.80.28,36 All analyses were

performed with two-tailed tests at the 5% significance level. The data were analyzed using

SPSS, version 22.0 (SPSS, Chicago, IL).

Results
Demographic and clinical characteristics of the subjects

A total of 22 subjects were enrolled in this study. Two patients were excluded because

they did not meet inclusion criteria. A sample size of 20 subjects was randomized and included

in the analysis to either a-tDCS (n=10) or s-tDCS (n=10) as presented in the flowchart (Figure

2).

---------------------------Insert figure 2----------------------------------

The clinical and demographic characteristics of the patients are presented in Table 1.

Baseline features were balanced between the treatment groups. In the guessing treatment

assessment, 19 patients (95.1%) believed received a-tDCS and one patient (5%) believed to

have received s-tDCS. The cumulative incidence of burning, tingling, itchiness, and redness in

the a-tDCS and s-tDCS were 25% and 17%, respectively (χ2=1.92; P = 0.165). While, the

cumulative incidence of a headache, neck pain, mood swings, and concentration difficulties

were reported in 7% and 16% of a-tDCS and s-tDCS, respectively (χ2= 3.97; P = 0.046). All

side effects were classified as mild.

--------------------Insert table 1-------------------------------------------

Impact of tDCS on global pain in the last 24 hours across 12 weeks of treatment (primary

outcome)

The mixed model (MMRM) revealed that a-tDCS compared to s-tDCS reduced pain

scores significantly in cumulative VAS mean across 12 weeks of treatment. We observed a

main effect for treatment (F[1]=213.37; P<0.001) and time (F[12]=7.66; P<0.001). However,

we did not observe a significant interaction of treatment group with time (F[12]=2.03; P=0.05).

The BDNF of baseline was inversely correlated with the improved in the pain scores across of

treatment [(F [1]=4.84; P=0.02), (β=-0.006; t=-2.47; P=0.01)]. That is, patients with higher

BDNF at baseline showed a larger reduction in the pain scores in the VAS at the treatment end.

In figure 3 are presented the cumulative means of daily pain score in the VAS during each
week according to treatment group. As can be seen, the a-tDCS group had significantly lower

scores of pain in VAS compared to the s-tDCS from the second-week until the treatment end

(P<0.001).

From the baseline to 4th week of treatment, the a-tDCS reduced the pain scores by 45.65%

[mean (SD) 7.25 (1.43) vs. 3.94 (1.14)] compared to 27.74% in the s-tDCS [mean (SD) 7.10

(1.81) vs. 5.13 (0.90)], respectively (t=2.61; P=0.01). The ES within group after 20 sessions of

a-tDCS as assessed by SDM was 2.31 (3.31/1.43) whereas in the s-tDCS was 1.08 (1.97/1.81).

At the end of treatment (after 60 sessions), a-tDCS reduced pain scores in the VAS to 2.75

(0.85) (a reduction of 62.06%), when compared to 5.33 (0.81) in the s-tDCS (a reduction of

24.92%) (t=6.94; P<0.0001). The ES within group after 60 sessions of a-tDCS was 3.14

(4.5/1.43), whereas in the s-tDCS was 0.97 (1.77/1.81). The effect size assessed by SDM

between groups at treatment end was 1.59 (2.58/1.62)

--------------------- Insert figure 2-----------------------------

Impact of tDCS on disability due to pain (secondary outcome)

The MMRM analysis revealed a significant main effect for Group (a-tDCS vs. s-tDCS)

and Time (baseline vs. treatment end) on total score of the B-PCP:S, as well as for each of their

three subscales that assess the following aspects related to pain: severity, disability, and the

emotional burden. Interaction terms were found significant for total B-PCP:S and for severity

and disability subscales, but not for emotional burden. The statistics are presented in Table 2.

The effect of treatment in these measures showed a large effect size, except for severity which

was moderate.

--------------------------Insert table 2-----------------------------------

Pairwise comparisons for Group and Time on total B-PCP:S are presented graphically

in Figure 4. From the baseline to treatment end the a-tDCS showed a reduction of 35.18 % in
the total score of the B-PCP:S [mean (SD) 75.99 (11.89) vs. 49.25 (21.26)] compared to

19.73% in the s-tDCS [mean (SD) 70.72 (14.30) vs. 56.76 (16.25)].

--------------------------Insert figure 4---------------------------

Impact of tDCS on analgesic use, psychophysical measures, psychological symptoms and

sleep quality (secondary outcomes)

Analgesic use during the 12 weeks of treatment occurred in 64% of patients sham-

treated, compared to 35% in the a-tDCS. The relative risk (RR) for the reduction in analgesic

use in the a-tDCS was 55% [RR=0.55 (95% CI 0.33-0.93), P<0.03]. In a-tDCS, 60% made a

clinically significant reduction in their codeine or tramadol dose compared to 30% in s-sham-

treated. While in total non-opioid analgesics a-tDCS 65.5% earned a clinically significant

decrease in the number of classes of medication they used compared to 25% in -sham-treated.

The mean (SD), at baseline and treatment end, with their respective ∆-value of the depressive

symptoms, pain catastrophizing, sleep quality, pain threshold and pain tolerance according to

the treatment group are presented in Table 3.

--------------------Insert table 3-------------------------------------------

The MANCOVA model was used to compare the effect of treatment between groups

assessed by ∆-values (post- to pre-treatment) of dependent variables (depressive symptoms,

pain catastrophizing, sleep quality and PPT). The results are presented in Table 4. This

analysis revealed significant effects of treatment, Pillai’s Trace’s F (6, 13) =4.95; P<0.01;

η²partial=0.69. The power this analysis was 92%.

-------------------------------Table 4---------------------------------

Discussion
 We showed that home-based HB-a-tDCS had a significant beneficial effect on the

cardinal symptoms of fibromyalgia, namely pain measures, disability due to pain,

psychological symptoms, sleep quality and disability due to pain. These findings provide

important data supporting the notion that an extended treatment regimen (60 sessions, which to

the best of our knowledge is the longest treatment in chronic pain to date) results in a large

effect size. It is likely that a cumulative effect over time was the case: after the first 20 sessions

pain scores reduced by 45.65%, whereas at the treatment end the reduction was of 62.06%,

with a large effect size (1.59).

The a-tDCS on the left DLPFC produced a top-down effect of considerable magnitude

on pain, disability due to pain and psychological symptoms. Its impact on the pain measures

agrees with a set of previous studies with anodal t-DCS applied on the M1.6,22,47 Although

these results are promising, the present evidence related to pain using tDCS over the DLPFC is

mixed. A meta-analysis found that in fibromyalgia, 5 to 10 sessions of anodal tDCS over the

DLPFC improved pain scores on the VAS and quality of life at treatment end. However, the

tDCS effect over DPLFC was transient, whereas the application over M1 persisted 60 days at

treatment end.60 Another meta-analysis found a decrease in the mean of the VAS score by

14.9% and 19.3%, with the tDCS applied over the M1 and the DLPFC, respectively.51 And, in

spinal cord injured patients, anodal tDCS applied over the M1 produced a standardized mean

difference of a moderate effect, in a short time, but the result was not maintained at follow-

up.35 Also, a meta-analysis found that healthy volunteers responded negatively to tDCS

compared with those with chronic pain, suggesting that the tDCS effect may be dependent

upon a specific population or medical condition.32 Thus, discrepancies among these findings

may be related to the number of tDCS sessions, genetic polymorphism of neuroplasticity

markers (e.g., BDNF)57, the severity of dysfunction in the neurobiology pathways involved in

pain processing and the pathophysiological pain mechanism (e.g., fibromyalgia, spinal injury,

etc.). We hypothesize that the number of sessions can be a factor involved in these differences.
This hypothesis found support in earlier studies that did not see improvement on pain after five

sessions of the tDCS over DLPFC in fibromyalgia,14 whereas a protocol that comprised ten

sessions reached a clinical benefit on pain scores and quality life.50 Another meta-analysis

indicated that the impact of tDCS to reduce the neuropathic pain consequent to spinal injury

was evident in those with more recent injury compared to those with long term chronic pain.35

The duration of secondary chronic pain, in which there is an underlying cause, permits us

estimate the pain duration with more precision compared to chronic primary pain, such as in

the fibromyalgia, in which cognitive symptoms ranged from around 50% to 90%, including

forgetfulness, distractibility, speech/language difficulties and disorganized thinking.48

According to previous studies, our findings highlight that the effect of tDCS on daily

pain scores is correlated with the neuroplasticity state, according to serum BDNF. This result

suggests that the direction of modulation depends on the state of the neural networks involved

in pain processing54 and it that the baseline neuroplasticity may be a determinant of inter-

individual variability of tDCS effects. The relevance this finding is to helps to comprehend the

influence of the dysfunctional neuroplasticity state on the response to this therapeutic approach.

Also, it stands up a new insight that can explain the variability in the reaction with tDCS

among patients with the same clinical diagnosis. However, it is not simple to translate this

finding related to the neuroplasticity state into the clinical setting. Although, it points out to a

new avenue to investigate how much the maladaptive neuroplasticity state can change the

impact of this type of therapy.

The predictable properties of BDNF on the effect of the a-tDCS is aligned with the

previous study that showed a similar relationship of the a-tDCS applied on the DLPFC in work

memory in the fibromyalgia25 as well on the postoperative recovery of the hallux valgus

surgery.6 The involvement of BDNF in the clinical effect of the a-tDCS is plausible since it is

capable of changing neuroplasticity mechanism involving the strengthening glutamatergic

synapses, while it weakens GABAergic synapses.13 However, we should interpret with

parsimony this result, because although the BDNF can be a marker to probe the dysfunctional

neuroplasticity, it does not permit to define whether it is an underlying pathophysiological

mechanism of the fibromyalgia or a disease severity state-dependent phenomenon.

In the same line, these findings highlight that the a-tDCS effect on pain scores was

cumulative and did not show a ceiling effect. The decrement in the pain scores across the

treatment, permit us to assume in an indirect way that it may be related to the a-tDCS effect in

the remapping of the disrupted neurochemical systems, underpinning the pathophysiology of

fibromyalgia. These effects are plausible based on the general pathophysiological mechanisms

of fibromyalgia25 and by extensive literature that related the impact of a-tDCS over M1 on the

pain with an imbalance of the excitability/inhibition in the circuitry involved in pain

processing.17 Thus, these findings give additional information that can help the clinician to

decide what is the best target to apply the tDCS (i.e.., M1 or DLPFC). Although at present the

literature is scarce to offer arguments to give support for the best target for the a-tDCS,

perhaps, the decision should be individualized taking into account symptoms associated with

disability for daily activities and the pathophysiology of chronic pain (i.e., fibromyalgia,

phantom pain, neuropathic pain, etc.). Also, we are conscious that, even though these results

are promising, further studies are needed for scientific validation.

The clinical impact of the a-tDCS on the left DPFC on depressive symptoms, pain

catastrophize and sleep quality. These results can be explained by upregulation of reactions to

positive emotional stimuli. In accordance, the previous study found that anodal stimulation

over left DPFC region improved the identification of positive emotional expressions.37

Whereas another study found that it may reduce the perceived degree of emotional valence for

negative emotional pictures40, and anger expressions induced for images.16 On the other hand,

the right DLPFC may be involved in the upregulation of negative emotional outcomes.

Treatment with high frequency (i.e., excitatory) using repetitive transcranial magnetic

stimulation (rTMS) over the right DLPFC resulted in impaired attention disengagement from a
threat (angry faces).16 Nevertheless, further studies are needed to clarify how stimulation of

both hemispheres improved the outcomes related to pain and disability in fibromyalgia.

The effects of a-tDCS to improving PPT, and HPTo are supported by an extensive

number of studies using tDCS to decrease pain.39,20,15 Although in the most part of studies the

site to apply the a-tDCS has been the M1,1,29,21 our results suggest that a-tDCS over the left

DLPFC might affect the sensory-discriminative pain processing. Likewise, a previous study

showed that the DLPFC stimulation improved the pain threshold. 17,46 The theoretical

background mechanism to explain the effect of the DLPFC stimulation on pain is it effects in

downstream circuits, to the anterior insula, hypothalamus, periaqueductal gray substance,

nucleus accumbens and rostroventral medulla.55 In the same way, the earlier study pointed out

the role of DLPFC in pain modulation, particularly on pain tolerance.43 Thus, our findings

related to the improvement in the PPT is aligned with the literature. However, we did not find

this effect on the HPT. Although we unknown a clear explanation for this negative result, a

possible reason to explain this differential effect on pain threshold is that the HPT evaluated by

the QST is sensitive to identified dysfunction in peripheral sensory neurons, which is a

dysfunction found in fibromyalgia.60 Also, this discrepancy between the pain threshold

measures can be explained by an error type II.

In the interpretation these results certain limitations should be borne in mind. First, they

can be extrapolated to women with fibromyalgia since we included only women to reduce

potential bias related to sex, who are prone to activation upon negative emotional responses

(i.e., stress, fear, and anxiety).48 Second, the secondary outcomes should be interpreted as

explanatory. Third, our results corroborate to an earlier study that validated this approach of

self-application for long term use of the tDCS at home, and we find results similar those trials

that the treatment was under direct supervision. Fourth, even though the tDCS device used in

the current study offers an efficient technical solution that permitted for medical engineers who

not involved in the patients’ care programmed the tDCS device according to randomization
sequence,19 most of the patients believed they received a-tDCS. Also, the pain scores reached

improvement of around 25% on the s-tDCS. These results suggest to the Hawthorne effect.33

Although this effect did not be determined by the electrical current showed a moderate

magnitude, the clinical benefits of active intervention showed a larger size effect in all

outcomes. Fifth, the lack of follow-up did not allow for the determination of long-term effects.

Finally, from a clinical standpoint, these findings give additional data to plan further studies

(phase III and IV trials) with large sample sizes to allow the clinical use of self-application at

HB-tDCS as a feasible and practical approach to use in the clinical setting.

In conclusion, these findings support not only the efficacy HB-a-tDCS but also the

application of a large number of sessions of tDCS to improve pain, psychological symptoms,

sleep quality, and disability due to fibromyalgia. Additionally; they suggest that serum BDNF

at baseline predicted the impact of the intervention on daily pain measures across the treatment.

Author Contributions

AB, FC, WC had substantial contributions to the conception or design of the work. MZ, PS,

DS, FF and WC drafted the work or revised it critically for important intellectual content. All

the authors agree and approve the final version of this work.

Conflict of Interest Statement

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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Legends of Figures

Figure 1. Timeline the study. The time point of assessments. Baseline: questionnaire to

assessed clinical and socio-demographic characteristics, analgesic use, heat pain threshold

(HPT) by Quantitative Sensory Testing [(QST) and pain pressure threshold (PPT).

Instruments: Fibromyalgia Impact Questionnaire (FIQ); State-Trait Anxiety Inventory (STAI-

E-T); Central Sensitization Inventory (CSI), for Brazilian population (CSI-BP); Beck

Depression Inventory- (BDI-II), Brazilian Pain catastrophizing Scale – BP-PCS; Pittsburgh

Sleep Quality Index (PSQI); B-PCP:S - Brazilian Portuguese version of the Profile of Chronic

Pain: Screen. Blood sample to dose the serum level of the brain-derivate-neurotrophic-factor

(BDNF).
Figure 2. Flowchart of study.
Figure 3. Cumulative means of daily pain score in the VAS of each week throughout the 12

weeks according to the two experimental groups. Error bars represent the standard error of the

mean. Asterisks (*) indicates a significant difference between the a-tDCS group and the s-

tDCS (p < 0.01). The comparisons were performed using a mixed analysis of variance model,

followed by the Bonferroni correction for multiple post hoc comparisons. Transcranial direct

current stimulation (tDCS).

Figure 4. Mean in the B-PCP:S - Brazilian Portuguese version of the Profile of Chronic Pain:

Screen total score to assess the disability due to pain from baseline to the 12th week at

treatment end, according to the two experimental groups. The error bars show the standard

error of the mean (SEM). Asterisks (*) positioned above the bars indicate significant

differences (P<0.01) within groups. (**) Indicates significant differences (P<0.01) between the

s-tDCS and the a-tDCS groups. All comparisons were performed by an analysis of Variance in

the Mixed Model, followed by the Bonferroni correction for post hoc multiple comparisons.
 Table 1. Epidemiological and clinical characteristics at baseline, according to the treatment
group, values are given as the mean (SD) or frequency (n=20).
p-
Characteristics a-tDCS (n=10) s-tDCS (n=10)
value
Age (years) 48.6 (8 – 59) 49.7 (45 - 54) 0.768
Body mass index (Kg/m ) 2
26.7 (5.5) 29.7 (5.2) 0.220
Level of education (years) 12.9 (5.0) 11.8 (3.4) 0.570
Time of fibromyalgia diagnosis (years) 5.75 (1.48) 6.62.(1.64) 0.310
Employed (yes/no) 6/4 6/4
Smoking (yes/no) 1/9 1/9
Alcohol use (yes/no) 2/8 2/8
Analgesic medication in use (yes/no) 10/0 8/2
History of anxiety or panic attacks diagnosis use (yes/no) 7/3 1/9
History of depression disorders use (yes/no) 6/4 3/7
Use drug active on the nervous system (yes/no)** 2/8 4/6
Selective Serotonin Reuptake Inhibitor in use (yes/no) 0/10 2/8
Tricyclic antidepressant (yes/no) 1/9 1/9
Benzodiazepine 1/9 1/9
History of chronic disease (yes/no) 5/5 3/7
Hypertension (yes/no) 4/6 1/9
Type 2 Diabetes Mellitus (yes/no) 0/10 1/9
Asthma (yes/no) 1/9 1/9
Central Sensitization inventory (CSI-BP) score 61.30 (±12.48) 55.70 (±13.76) 0.967
State-Trait Anxiety Inventory – State 31.1 (±3.5) 29.6 (±9.4) 0.236
State-Trait Anxiety Inventory – Trait 25.5 (±2.2) 21.9 (±4.6) 0.032
Pittsburgh Sleep Quality Index – PSQI 10.8 (6.0 –15.0 ) 10.5 (4.0 – 17.0) 0.899
33.6 (19.0 – 24.9 (11.0 –
0.163
Pain Catastrophizing Scale – PCS 47.0) 38.0)
Fibromyalgia impact questionnaire – FIQ 71.7 (12.0) 63.9 (21.5) 0.687
Pain on visual analogue scale (VAS) 7.25 (1.43) 7.22 (1.81) 0.946
Pain pressure threshold (PPT) 2.8 (1.9 – 4.2) 3.2 (2.5 – 4.3) 0.398
Profile of chronic pain: screen for a Brazilian population (B- 60.3 (32.5 – 63.4 (27.9 –
0.512
PCP:S) 94.8) 94.5)
B-PCP:S - Severity 20 (11.5 – 29.0) 20.4 (8,5 – 30.0) 0.501
B-PCP:S - Interference 24.9 (13.0 – 42) 27.4 (4.0 – 57.9) 0.512
B-PCP:S - Emotional Burden 15.3 (8.0 – 25.0) 15.5 (3.0 – 28.0) 0.501
BDNF – Brain-derived neurotrophic factor 35.43 (27.39) 32.27 (31.43) 0.656
*Patients could have none or more than one diagnostics according Central Sensitization Inventory.
**Some patients were using more than one type of drug.
Table 2. Effects of treatment on disability due to pain base in the total score of the B-PCP:S and
its subscales between Groups: Mean (standard deviation, SD), percentage on mean change before (B) to
after (A) treatment, mean difference with the confidence interval (95% CI) and effect size (ES) (n = 20).
Mean (SD) Mean (SD) Percentage on Mean difference Df F P ES
before (B) after (A) mean change change (B to A)
treatment treatment (B to A) $ s-tDCS vs. a-tDCS
Secondary outcome
Treatment effect on disability due to pain during 12 weeks of follow up period
B-PCP:S - total score†
a-tDCS 75.99 (11.83) 36.88 (5.76) -50.79 (8.12) -25.50 (-42.50 to -8.50)
s-tDCS 70.72 (14.30) 49.78 (8.74) -25.29 (24.26)
Main effect of treatment 1 8.65 0.005 1.47
Time 2 68.61 <0.001
Interaction group vs. time 2 4.83 0.01
B-PCP:S pain severity †
a-tDCS 56.33 (16.23) 49.89 (14.62) -35.15 (7.40) -12.40 (-23.08 to -1.46)
s-tDCS 55.85 (14.63) 38.11 (19.86) -22.75 (14.26)
Main effect of treatment 1 9.20 <0.001 0.59
Time 2 83.23 <0.001
Interaction group vs. time 2 1.83 0.02
B-PCP:S interference in daily life activities †
a-tDCS 32.60 (6.20) 16.85 (3.23) -46.65 (13.27) -40.76 (-65.06 to -16.47)
s-tDCS 28.00 (6.91) 24.35 (4.88) -5.88 (34.07)
Main effect of treatment 1 5.83 0.01 1.53
Time 2 17.09 <0.001
Interaction group vs. time 2 7.64 <0.001
B-PCP:S emotional burden †
a-tDCS 17.70 (5.10) 10.90 (3.12) -35.41 (21.90) -48.06 (-88.51 to -7.61)
s-tDCS 16.90 (6.13) 16.15 (3.60) 13.06 (26.80)
Main effect of treatment 1 7.46 0.009 1.45
Time 2 4.42 0.01
Interaction group vs. time 2 2.89 0.06
B-PCP:S - Brazilian Portuguese version of the Profile of Chronic Pain: Screen total score. Degrees of freedom (Df)
$ Mean difference in the on mean change before (B ) to after (A) between treatment groups (a-tDCS vs. s-tDCS).
† Mixed ANOVA model. Mean difference groups
Effect size (ES) (Mean difference a-tDCS vs. s-tDCS)/Standard deviation on s-tDCS] 12 weeks after conclude the treatment.
The ES was computed by the standardized difference mean (SDM) defined as small if lower than 0.20 to 0.49; moderate if
between 0.50–0.79; and large if larger than 0.80. 31,40
Table 3. depressive symptoms, pain catastrophizing, sleep quality, pain threshold and pain

tolerance at baseline and treatment end according to s-tDCS or a-tDCS groups. Data are

presented as the mean and standard deviation (SD) (n=20).

s-tDCS (n=10) a-tDCS (n=10)

Mean (SD) ∆-value Mean (SD) ∆-value t P
Beck Depressive Inventory – II (BDI II)
20.50 (5.63) 1.00 (18.84) 27.10 -15.30 (9.38) -2.11 .04
Baseline (12.21)
End 21.50 (6.60) 11.80 (5.63)
treatment
Brazilian Portuguese Pain Catastrophizing Scale – BP-
PCS
24.90 -2.40 (18.27) 33.90 -20.80 (14.36) -2.50 .02
Baseline (13.81) (14.67)
End 22.50 (7.74) 13.10 (5.70)
treatment
Pittsburg Sleep Quality Index (PSQI)
Baseline 24.60 (7.57) -7.90 (9.15) 27.50 (7.63) -19.60 (10.04) -2.72 .01
End 16.70 (3.74) 7.90 (7.44)
treatment
Pain pressure threshold (kgf )
Baseline 3.27 (1.15) -.25 (1.16) 2.89 (0.79) 1.25 (0.86) 3.29 .00
End 3.02 (0.72) 4.14 (0.73)
treatment
Heat pain threshold (oC)
Baseline 36.40 (3.10) -0.62 (2.92) 37.70 (2.74) 0.63 (1.76) 1.16 .26
End 35.86 (1.92) 38.86 (2.39)
treatment
Heat pain tolerance (oC)
Baseline 45.12 (4.42) -2.23 (3.66) 42.60 (4.31) 2.64 (3.74) 2.94 .00
End 42.89 (3.32) 45.27 (2.52)
treatment
* Correspond to comparisons of ∆-value by the t-test for independent sample.
Table 4. MANCOVA to compare the effect of treatment between groups with ∆-values
depressive symptoms, pain catastrophizing, sleep quality, PPT and pain tolerance (n=20).

Corrected model Type III df Mean F Sig. Partial

Sum of Square Eta
Squares Squared
Dependent Variable
∆-Beck Depressive Inventory – II (BDI II) 1328.450a 1 1328.450 4.490 .048 .200
b
∆- Brazilian Portuguese Pain Catastrophizing Scale – PCS 1692.800 1 1692.800 6.264 .022 .258
c
∆-Pittsburg Sleep Quality Index (PSQI) 684.450 1 684.450 7.407 .014 .292
d
∆- Pain pressure threshold (kgf ) 11.312 1 11.312 10.834 .004 .376
o e
∆- Heat pain tolerance ( C) 118.585 1 118.585 8.642 .009 .324
Intercept
∆-Beck Depressive Inventory – II (BDI II) 1022.450 1 1022.450 3.455 .079 .161
∆- Brazilian Portuguese Pain Catastrophizing Scale – PCS 2691.200 1 2691.200 9.959 .005 .356
∆-Pittsburg Sleep Quality Index (PSQI) 3781.250 1 3781.250 40.920 .000 .695
∆- Pain pressure threshold (kgf ) 4.952 1 4.952 4.743 .043 .209
o
∆- Heat pain tolerance ( C) .841 1 .841 .061 .807 .003
Treatment group
∆-Beck Depressive Inventory – II (BDI II) 1328.450 1 1328.450 4.490 .048 .200
∆- Brazilian Portuguese Pain Catastrophizing Scale – BP- 1692.800 1 1692.800 6.264 .022 .258
PCS
∆-Pittsburg Sleep Quality Index (PSQI) 684.450 1 684.450 7.407 .014 .292
∆- Pain pressure threshold (kgf ) 11.312 1 11.312 10.834 .004 .376
o
∆- Heat pain tolerance ( C) 118.585 1 118.585 8.642 .009 .324
a. R Squared = .200 (Adjusted R Squared = .155)
b. R Squared = .258 (Adjusted R Squared = .217)
c. R Squared = .292 (Adjusted R Squared = .252)
d. R Squared = .376 (Adjusted R Squared = .341)
e. R Squared = .070 (Adjusted R Squared = .018)