ORIGINAL RESEARCH ARTICLE

Effects of High-Frequency Neuronavigated Repetitive Transcranial

Magnetic Stimulation in Fibromyalgia Syndrome
A Double-Blinded, Randomized Controlled Study
Ibrahim Bilir, MD, Ayhan Askin, MD, Ilker Sengul, MD, and Aliye Tosun, MD

Objective: The primary aim of the study was to investigate the effect
of 10-Hz repetitive transcranial magnetic stimulation to the left dorso- What Is Known
lateral prefrontal cortex on pain in fibromyalgia. Secondary aims were • The pathophysiology of fibromyalgia is still unknown.
to determine its effects on stiffness, fatigue, quality of life, depression/ The most acceptable theory is the central sensitization
anxiety, and cognitive functions. that includes altered pain processing based on pe-
Design: Twenty participants were randomized into two groups. Group ripheral and central nervous system influences. Re-
A received 10-Hz repetitive transcranial magnetic stimulation to left cently, a growing number of studies were performed
dorsolateral prefrontal cortex and group B received sham stimulation. on modulation of central pain pathways of fibromyal-
Visual analog scale for pain, visual analog scale–stiffness, Fibromyal- gia. The promising treatment option in this regard is
gia Impact Questionnaire, and Fatigue Severity Scale were assessed at seen as neuromodulation techniques such as repetitive
the baseline, 2nd, and 6th weeks, whereas Hospital Anxiety Depres- transcranial magnetic stimulation.
sion Scale and Addenbrooke’s cognitive examination were assessed What Is New
at the baseline and 6th week. • High-frequency repetitive transcranial magnetic stim-
Results: There was no significant difference in visual analog scale– ulation to the left dorsolateral prefrontal cortex may
pain and Fatigue Severity Scale within and between groups over time not have a significant beneficial effect on pain, stiff-
(P > 0.05). In group A, significant improvement was found in visual ness, fatigue, quality of life, anxiety-depression, and
analog scale–stiffness and fibromyalgia impact questionnaire at the cognitive state in patients with fibromyalgia syndrome.
2nd week in comparison to the baseline (P < 0.05). However, no sig-
nificant difference was detected in comparison with group B. There
was no significant change in Hospital Anxiety Depression Scale in men.3 It has substantial impacts on quality of life, physical
scores between and within groups. All cognitive measures were similar functioning, and social-occupational productivity; therefore,
in terms of differences from baseline between the groups (P > 0.05). financial costs are an economic burden to these patients.4
Conclusions: High-frequency repetitive transcranial magnetic stimu- The pathophysiology of this syndrome is still unknown, but ge-
lation to the left dorsolateral prefrontal cortex did not show any signif- netic predisposition, hypothalamic-pituitary-adrenal axis dys-
icant beneficial effect on pain, stiffness, fatigue, quality of life, mood, function, environmental factors, autonomous dysfunction,
and cognitive state over sham stimulation. metabolic factors, neuropathies, and neuromodulation are
Key Words: Fibromyalgia, Transcranial Magnetic Stimulation, all being considered to be involved in the onset and course
Neuronavigation, Pain, Fatigue, Cognition of the disease.2,5 As we know today, the most acceptable theory
is the central sensitization that includes altered pain processing
(Am J Phys Med Rehabil 2021;100:138–146) based on peripheral and central nervous system influences.5,6
The purpose of FMS management is to reduce pain, im-
prove sleep, and restore physical, emotional, and mental func-
ibromyalgia syndrome (FMS) is a chronic pain condition tion, thereby improving overall quality of life. However, there
Ffatigue,
characterized by widespread pain, stiffness, overwhelming
sleep disturbance, mood alterations, cognitive dys-
is no criterion standard treatment method because of the diffi-
culty of the diagnosis of the disease as well as the unknown
function, and impaired quality of life and daily function.1,2 Fi- pathophysiology.2,7 High-quality evidence supports multidisci-
bromyalgia syndrome is present in as much as 0.2%–6.6% of plinary approach that includes nonpharmacological therapies (ed-
the general population and is more common in women than ucation, exercise, cognitive behavioral therapy, physical-therapy

From the Department of Physical Medicine and Rehabilitation, Katip Çelebi Univer- IB and AA did the conception. IB, AA, and IS did the design. AA did the
sity, Faculty of Medicine, Izmir, Turkey. supervision. AT did the fundings. IB, AA, and AT did the data collection and
All correspondence should be addressed to: Ayhan Askin, MD, Katip Çelebi processing. IS did the analysis and interpretation. IB and AA did the literature
Üniversitesi Atatürk Eğitim ve Araştırma Hastanesi, Fiziksel Tıp ve review. AA and AT did the writing. IB, AA, IS, and AT did the critical review.
Rehabilitasyon A.D., Basın Sitesi Yeşilyurt, Izmir, Turkey. Financial disclosure statements have been obtained, and no conflicts of interest have
This work was supported Izmir Katip Çelebi University Scientific Research been reported by the authors or by any individuals in control of the content of
Project fund. this article.
The authors declared that the research was conducted according to the principles of Supplemental digital content is available for this article. Direct URL citations appear
the World Medical Association Declaration of Helsinki “Ethical Principles for in the printed text and are provided in the HTML and PDF versions of this article
Medical Research Involving Human Subjects” (amended in October 2013). on the journal’s Web site (www.ajpmr.com).
University local Research Ethics Committee Approval number: 14.03.2019/25. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Written informed consent was obtained from the patients who participated in ISSN: 0894-9115
this study. DOI: 10.1097/PHM.0000000000001536

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Volume 100, Number 2, February 2021 rTMS in Fibromyalgia Syndrome

agents, acupuncture, multicomponent treatments) and pharmaco- Therefore, this study primarily aimed to evaluate the effec-
logical therapies (tricyclics, serotonin norepinephrine reuptake tiveness of 10-Hz neuronavigated rTMS to the left DLPFC on
inhibitors, and gabapentinoids) to achieve optimal management pain in FMS. Secondary aims were to determine its effects on
results.7–9 Recently, a growing number of studies are performed stiffness, fatigue, quality of life, depression/anxiety, and cogni-
on modulation of central pain pathways of FMS. The promising tive functions.
treatment option in this regard is seen as neuromodulation tech-
niques such as transcranial magnetic stimulation (TMS).10,11 PATIENTS AND METHODS
Repetitive TMS (rTMS) is a safe and noninvasive method
of stimulating neurons in the cerebral cortex. It is used to in- Participants
duce changes in brain activity that can produce aftereffects
Participants were recruited from physical medicine and re-
on the brain.12,13 Repetitive TMS modulates cortical plasticity,
which is called the functional rearrangement of connections habilitation outpatient clinics of a university hospital. Twenty
patients (mean ages = 45.25 ± 9.08 yrs, range = 29–64 yrs;
between neurons and neuronal features.12,13 It is generally as-
20 female patients) with FMS who met the following inclusion
sumed that rTMS-induced effects may closely relate to synaptic
plasticity such as long-term potentiation or depression.13,14 An criteria were included in the study: (1) adults (age between
18–65 yrs); (2) diagnosis of FMS according to 2016 Fibromy-
aftereffect induced by rTMS depends on stimulation frequency.
algia diagnostic criteria23,24 (see Supplementary Appendix A,
High-frequency rTMS at 5 Hz or higher transiently increases
Supplemental Digital Content 1, http://links.lww.com/PHM/
cortical excitability (i.e., long-term potentiation–like), whereas
B78); (3) visual analog scale–pain score of 4/10 or greater;
stimulation at 1 Hz decreases cortical excitability (long-term
and (4) stable treatment (any kind of treatment including phar-
depression–like).14 Repetitive TMS also affects brain activities
macotherapy, physical therapy, psychotherapy, interventional
related to pain modulation and processing. Therefore, its use in pain
pain treatments) for at least last 3 mos. All participants were
syndromes is increasing.15,16 In addition, rTMS offers potential for
questioned for absolute/relative contraindications (e.g., metal-
clinical application in a variety of neurological, psychiatric dis-
lic implant, cardiac pace, pregnancy, and medications) for
eases (e.g., stroke, Parkinson disease, dementia, depression).16–18
Besides, the success of these treatments is enhanced by using TMS treatment. Pregnancy was excluded by laboratory testing
in premenopausal participants. The following patients were ex-
neuronavigation systems that accurately position the coil on a
cluded: if they had a clinical condition to be contraindicated for
target and keep the coil in the correct place during the session.19
Although there are many randomized clinical trials reveal- TMS (e.g., metallic implant, cardiac pace, pregnancy, lactation,
epilepsy, head trauma, history of cranial operation); significant
ing beneficial effects of rTMS in FMS, there is no consensus
medical or psychiatric illness including malignancy, major de-
regarding the exact efficacy or optimal parameters of stimula-
pression, personality disorder, history of substance, or alcohol
tion. Therefore, it is very important to determine whether
abuse; major orthopedic/neurological problems that limit daily
rTMS is sufficiently effective on the clinical findings of pa-
life activities; pregnancy/breastfeeding; concomitant inflamma-
tients with FMS. Studies have generally focused on
tory rheumatic diseases, autoimmune diseases, or other painful
high-frequency (>5 Hz) stimulation of the left primary motor
cortex (M1) or left dorsolateral prefrontal cortex (DLPFC). disorders, and patients who have received TMS treatment before.
Stimulation parameters of these studies are quite different, Study Design and Ethics
and neuronavigation systems are rarely used in target selection. This is a single-center, prospective, randomized, double-
A recent meta-analysis evaluated a few randomized, controlled, blinded, sham-controlled study in two-arm parallel-group de-
double-blind studies, which mainly investigated pain, quality sign (Fig. 1). This study conforms to all Consolidated Stan-
of life, and mood in FMS. Knijnik et al.11 reported that there dards of Reporting Trials guidelines and reports the required
was no significant difference between sham or active rTMS information accordingly (see Supplemental Consolidated Stan-
for reducing pain or depression, but active rTMS was associ- dards of Reporting Trials Checklist, Supplemental Digital
ated with a significant improvement on quality of life. They Content 2, http://links.lww.com/PHM/B79). Participants were
also stated that future research is needed to clarify the potential informed about the study and provided written informed con-
difference in clinical effects based on the stimulation area (M1 sents. The protocol was performed in accordance with the eth-
vs. DLPFC) and different treatment protocols (number of days, ical standards laid down in the 1964 Declaration of Helsinki
duration of each stimulation, frequency). Saltychev and and approved by the local research ethics committee (Approval
Laimi20 revealed moderate evidence that rTMS is not more ef- Number: 14.03.2019/25). This study was registered on http://
fective than sham in reducing the severity of pain in FMS. Hou www.clinicaltrials.gov with ID NCT03909009.
et al.10 suggested that M1 stimulation may be better in pain re-
duction and the DLPFC may be better in depression improve- Demographics
ment. On contrary to this study, in their recent guideline At baseline, demographic information including age, sex,
updates, Lefaucheur et al.21 reported that high-frequency weight, height, body mass index, dominant side, marital status,
rTMS of the left DLPFC is more efficacious on pain, whereas education level, occupation, disease duration, additional dis-
high-frequency rTMS of the left M1 is more efficacious on the eases, smoking, and alcohol use, drugs used for FMS treatment
quality of life. In addition, there are very few studies investigat- were questioned.
ing the effect of TMS treatment on cognitive dysfunction,
which is an important problem in FMS.22 For all these reasons, Randomization and Blinding
it is clear that there is still a need for further qualified studies on Randomization was performed using computer-generated
the exact clinical effects of rTMS treatment in FMS. block randomization with 1:1 allocation between the active

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Bilir et al. Volume 100, Number 2, February 2021

FIGURE 1. Illustration of the study design.

rTMS group (group A) and the sham-control group (group Secondary Outcomes
B) by an independent researcher who was not involved in the The secondary outcome measures were stiffness, quality
rTMS treatment sessions, patient selection, or clinical evalua- of life, fatigue, mood, and cognitive state.
tions. Two different researchers conducted other parts of this
double-blind study. One of the researchers performed patient
selection and interventions. The second researcher was blinded Stiffness Severity
about the distribution of groups, patient selection, and inter- Stiffness, one of the main symptoms of FMS, has been
ventions. The blind investigator performed patient evaluations used as an outcome measure in a few rTMS studies. In addi-
at the beginning of treatment, at the end of the 2nd, and 6th tion, in these studies, it was evaluated with VAS as a subscore
weeks. Patients were also blinded during the study. of the validated FIQ. Therefore, severity of stiffness was
assessed on a 10-cm line (0 = no stiffness, 10 = severe stiffness)
at baseline, at 2nd, and at the end of treatment (6th week) in this
Outcome Assessment and Data Collection study.25,28,29
After recording general demographic data, clinical assess-
ments were performed. All clinical outcome measures were Fibromyalgia Impact Questionnaire
assessed by an experienced researcher who was familiarized Functional health status and quality of life of the partici-
with the scales and tests used in this study and who was blinded pants were assessed with the FIQ, which measures 10 different
about the group assignment. The clinical assessments consisted features (physical functioning, missed days of work, depres-
of six main sections: (1) pain severity (VAS-pain); (2) stiffness sion, anxiety, feeling good, morning tiredness, pain, stiffness,
severity (VAS-stiffness); (3) Fibromyalgia Impact Questionnaire fatigue, and well-being over the past week). The FIQ has been
(FIQ); (4) Fatigue Severity Scale (FSS); (5) Hospital Depression most commonly used in clinical studies, and it is also a vali-
Anxiety Scale (HADS); and (6) Addenbrooke’s Cognitive dated instrument developed to measure FMS patient status,
Examination–last revised version (ACE-R). progress, and outcomes. The total FIQ score is maximum
100 points. Higher scores indicate lower functionality level.
Primary Outcomes In this study, total score of FIQ was evaluated at baseline, at
the end of the 2nd, and 6th weeks.30,31
The primary outcome measure was pain severity evaluated
with VAS. Visual analog scale is a psychometric measuring in-
strument designed to document the severity of the disease-related Fatigue Severity Scale
symptoms. It is widely used in many FMS studies because of Severity of fatigue was evaluated with FSS, a nine-item
its simplicity and adaptability to various populations. The scale self-report questionnaire scale. It has been proved to be valid
shows good statistical properties for the evaluation of chronic and reliable to detect presence and severity of fatigue in FMS.
pain conditions.15,25,26 In this study, the severity of the pain ex- Each item of this scale consists of statements that are scored
perienced at rest was assessed on a 10-cm line (0 = no pain, on a 7-point Likert type scale ranging from 1 to 7. Total FSS
10 = severe pain) at baseline, at 2nd week, and at the end of score is calculated as the mean value of nine items. It was assessed
treatment (6th week).27 at baseline, at the end of the 2nd, and 6th weeks in this study.32

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Volume 100, Number 2, February 2021 rTMS in Fibromyalgia Syndrome

Hospital Anxiety and Depression Scale Neuro-MEP-Micro2-channel Electromyogram (EMG; Neurosoft,

Hospital Anxiety and Depression Scale is an assessment Russia) device. The RMT was defined as the minimum stimu-
tool developed to identify the risk of anxiety and depression lation intensity to evoke a MEP greater than 50 μV in at least 5
and measure its level and change of severity. Its subscales are of 10 single-pulse TMS trials applied to the left primary motor
anxiety and depression. It contains 14 questions in total, in- cortex (M1). The EMG signals were recorded from electrodes
cluding 7 (odd numbers) measuring anxiety and 7 (even num- placed over the first dorsal interosseous muscle of the right
bers) measuring depression. The lowest and highest scores that hand, with a circular ground electrode placed over the wrist.
a person can obtain from either subscale are 0 and 21, respec- Repetitive TMS therapy was applied under the guide of
tively. The HADS shows a clear bifactor structure among FMS neuronavigation with the following parameters: target-left
patients, and it was used in many FMS studies in the literature. DLPFC, with the 90% of the RMT, 10-Hz stimulation for
Hospital Anxiety and Depression Scale was evaluated at base- 5-sec intervals (on) with 25-sec intertrain intervals (off ),
line and at the 6th week of the study.33–35 15 mins, and 1500 pulses. The stimulation parameters of the
study protocol are within the safety limits recommended for
Addenbrooke’s Cognitive Examination Revised rTMS.40 For sham stimulation, reversely positioned probe
The Mini-Mental State Examination (MMSE), as well as was localized over the left DLPFC and stimulus intensity was
the clock drawing test with different scoring methods, has been set to 1% of the RMT (to ensure the clicking sound without ac-
recognized as a reliable screening method for cognitive impair- tual stimulation of the brain). All patients were rTMS naive, so
ment in patients with FMS, although they are not specific for they could not recognize the sham or active treatment tech-
pain syndromes. Addenbrooke’s Cognitive Examination–last niques. Besides, a sufficient time was left between subsequent
revised version is a brief, useful cognitive test that contains patients; therefore, none of the patients saw each other during
MMSE as well as giving a total score with subscores of differ- rTMS treatments.
ent cognitive domains. There is also Turkish adaptation. It con-
sists of five basic sections: attention and orientation (max. 18
Sample Size
points), memory (max. 26 points), verbal fluency (max. 14
points), language (max. 26 points), and visual-spatial abilities Sample size calculation was performed with G*Power
(max. 16 points). The highest score that can be obtained is software (Version 3.1.9.2; G*Power, Germany). A priori sam-
100. It is considered useful in discriminating cognitively nor- ple size based on the work of Tekin et al.41 was calculated on
mal subjects from patients with mild cognitive impairment. the basis of changes in pain scores (VAS) evaluated before
Addenbrooke’s Cognitive Examination–last revised version and after the treatment. It was determined that at least 5, a total
was assessed at baseline and at the 6th week of our study.36–38 of 10 patients in each group should be included in the study ac-
cording to 80% power, 5% margin of error, and 1.73 effect size.
Considering the statistical methods and the drop off patients
Interventions from the study, the sample size was planned as at least
Twenty patients were randomized into two groups. After 10 patients in each group and at least 20 patients in total.
randomization, group A received 10 sessions daily rTMS
(5 d/wk, 2 wks) as “induction phase” followed by a “mainte-
nance phase” consisting of four sessions weekly (1 day/wk, Statistical Analysis
4 wks). Group B received sham treatment at the same schedule. Database management and statistical analyses were per-
formed by an independent researcher. The statistical analysis
Neuronavigated Repetitive TMS was performed by SPSS Statistics 22.0 (IBM Corp, Armonk,
Brain images for participants were performed on a 1.5 T NY) software. As the descriptive statistics, the number of units,
magnetic resonance scanner (GE Sigma HDxt; General Elec- percent, mean ± SD, and median (interquartile range) values
tric Medical Systems, Milwaukee, WI) using an eight-channel were given. Distributions of continuous variables were evalu-
head coil. Magnetic resonance imaging scans of each partici- ated using the Shapiro-Wilk test and Q-Q plots. According to
pant’s brain were imported to the 3D-guided neuronavigation the normality tests, a two-sample t test or Mann-Whitney U test
device (NeNa-Neural navigator, The BrainTRAK; Brain Sci- was used to compare two groups concerning numerical variables
ence Tools BV, Utrecht, the Netherlands). Then, brain segmenta- at baseline. In terms of categorical variables, the χ2 test was used
tion and the creation of stimulation target were performed. The to compare the groups. To study the effects of the interventions
location of the left DLPFC was determined by an experienced on VAS-pain, VAS-stiffness, FIQ, and FSS, two-way (group 
researcher in accordance with the literature.39 These data were time) repeated measures analysis of variance was used. Accord-
saved and used to target the left DLPFC in the future sessions. ing to the results of two-way repeated measures analysis of var-
The position of the TMS coil and the patient’s head was iance tests, one-way repeated measures analysis of variance was
tracked using the BrainTRAK, a magnetic position tracking performed to investigate the changes over time in each group.
device built into the Neural Navigator. The assumption of normality for analysis of variance tests was
A Neuro-MS/D TMS device (Neurosoft, Russia) with a assessed by checking the residuals. In the comparison of HADS
figure-of-eight coil was used for rTMS. Participants were and ACE-R, which were measured at two different times, the
seated in a comfortable chair with headrest and armrests and comparisons between groups were performed by using a
were told to rest both hands and upper limbs on top of their two-sample t test or Mann-Whitney U test (whichever was ap-
thighs. At the beginning of each session, the resting motor propriate). Within-group comparisons for HADS and ACE-R
threshold (RMT) of each participant was determined using were conducted by using the paired t test or Wilcoxon test

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Bilir et al. Volume 100, Number 2, February 2021

FIGURE 2. Flow diagram of the study.

(whichever was appropriate). P values of less than 0.05 were these outcome measures were statistically significant (P = 0.015).
considered significant. Within-group comparisons, only in group A, there was a statis-
tically significant decrease at the 2nd week compared with the
RESULTS

Demographic and Clinical Characteristics of TABLE 1. Demographic and clinical characteristic of the groups
the Patients Group A Group B
Twenty-eight patients were evaluated for participation in (n = 10) (n = 10) P
the study. Eight patients were excluded. No adverse events were Age, yr 46.70 ± 9.06 43.80 ± 9.37 0.490
reported by any of the participants, and all participants com- Body mass index, kg/m2 29.42 ± 7.31 25.2 ± 3.74 0.134
pleted the trial. A flow chart of the study is shown in Figure 2. Disease duration, mo 60 (24–63) 66 (48.73–66) 0.179
The mean ages of the total study sample were 45.25 ± 9.08 yrs Dominant extremity, 9/1 (90/10) 9/1 (90/10) 1.0
(range = 29–64 yrs; 20 female patients). There was no statisti- right/left, n (%)
cally significant difference between demographical character- Marital status, 10/0 (100/0) 8/2 (80/20) 0.474
istics of the patients (P > 0.05). Although educational status married/single, n (%)
was statistically similar between the groups, education levels Occupation, worker/not 2/8 (20/80) 2/8 (20/80) 1.0
of patients in group A were lower. No statistically significant working, n (%)
difference was found in baseline clinical characteristics except Educational status, n (%) 0.273
for MMSE and ACE-R subscores (attention-orientation, Primary school 9 (90) 6 (60)
visual-spatial abilities). The MMSE and ACE-R (attention- High school 1 (10) 3 (30)
orientation and visual-spatial abilities) scores were signifi- University 0 1 (10)
cantly higher in group B (P = 0.017, P = 0.036, and Comorbidities, n (%) >0.999
P = 0.021, respectively). Demographical and baseline clinical Diabetes mellitus 2 (20) 0
characteristics of the patients are given in Table 1 and Table 2. Hypertension 4 (40) 2 (20)
Migraine 1 (10) 1 (10)
Clinical Outcome Measures Smoke 2 (20) 3 (30) >0.999
All of the participants continued directly to the mainte- Alcohol 1 (10) 0 >0.999
nance phase because all showed improvements in at least one Medications, n (%) 0.307
of the outcome measures. The effects of treatment method Duloxetine 4 (40) 3 (30)
and duration on VAS-pain and FSS were not statistically signif- Pregabalin 1 (10) 3 (30)
icant (P > 0.05). In addition, changes in VAS-pain and FSS Venlafaxine 1 (10) 0
over time did not differ between the treatment groups Pregabalin + duloksetin 2 (20) 0
(P > 0.05). When the VAS-stiffness and FIQ were examined, Values are n (%), mean ± SD, or median (interquartile range).
the effects of the treatment method on the VAS-stiffness and Group A, active TMS; Group B, sham.
FIQ were not significant (P > 0.05) but the effects of time on

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Volume 100, Number 2, February 2021 rTMS in Fibromyalgia Syndrome

differences in ACE-R total score (P = 0.046) and attention

TABLE 2. Baseline clinical characteristics of the groups
scores (P = 0.003), all cognitive measures were similar in terms
Group A (n = 10) Group B (n = 10) P of differences from baseline (P > 0.05). Comparisons of
changes in HADS and ACE-R scores over time in the groups
VAS (pain) 7.20 ± 1.75 7.40 ± 1.35 0.778 are shown in Table 4.
VAS (stiffness) 7.40 ± 1.58 7.60 ± 1.17 0.751
FIQ 65.86 ± 8.27 66.44 ± 11.40 0.898 DISCUSSION
FSS 5.28 ± 1.23 6.08 ± 1.11 0.143 The results of this randomized sham-controlled study re-
HADS (total) 19.30 ± 8.14 22.90 ± 5.61 0.264 vealed significant improvements in stiffness, quality of life,
Anxiety 11.40 ± 5.42 13.90 ± 3.21 0.226 and ACE-R memory scores of the FMS patients with 14 ses-
Depression 7.90 ± 3.28 9.00 ± 3.27 0.462 sions of 10-Hz rTMS (90% of the RMT, 1500 pulses/session,
ACE-R (total) 62.50 ± 18.80 76.90 ± 11.17 0.052 10 sessions daily, and 4 sessions weekly) to the left DLPFC.
MMSE 22.10 ± 5.22 27.10 ± 2.56 0.017 However, none of the improvements in that clinical outcome
Attention and 13.5 (9.25–16.5) 17.5 (15–18) 0.036 measures were different from the sham group. Moreover, both
orientation
mood and cognitive measures were similar in terms of differ-
Memory 10.40 ± 3.92 13.20 ± 3.71 0.118
ences from baseline between the groups. High-frequency
Verbal fluency 8.20 ± 3.19 9.60 ± 3.95 0.395
rTMS to the left DLPFC did not show any significant benefi-
Language 22 (10.5–25) 23.5 (20.75–25.25) 0.270
cial effect on pain, stiffness, fatigue, quality of life, anxiety-
Visual-spatial abilities 13 (11–14.25) 15 (13.75–16) 0.021
depression, and cognitive state in FMS over sham stimulation.
Values are mean ± SD or median (interquartile range). The values in bold Although the pathophysiology of FMS has not been fully
are significantly different at the P < 0.05 level. determined yet, it is known as a chronic pain condition charac-
Group A, active TMS; Group B, sham. terized by central sensitization that affects pain modulatory
system. Several studies have been carried out considering that
rTMS may have beneficial effects on FMS treatment by alter-
baseline in VAS-stiffness and FIQ scores (P = 0.004, P = 0.005, nating cortical excitability of brain structures that are related
respectively). However, no significant difference was found in to pain modulation and processing.15,21,42 M1 and DLPFC
comparison with group B (P > 0.05; Figs. 3, 4). Comparisons have important effects on cognitive-sensory networks, top-down
of VAS-pain, VAS-stiffness, FIQ, and FSS scores according to control of pain, releasing of opioids, and modulation of the
treatment groups and time are shown in Table 3. frontolimbic system.43,44 Therefore, generally, left M1 and left
Anxiety scores were significantly decreased in group B at DLPFC were targeted as the stimulation sites. Passard et al.28
the 6th week compared with the baseline (P = 0.045). How- revealed that rTMS of the M1 induced a long-lasting decrease
ever, the level of statistical significance was close to 0.05. in pain and improved quality of life in patients with FMS, with-
Other than this, there was no statistically significant difference out affecting mood. Mhalla et al.29 reported that 10-Hz rTMS
in terms of the changes in anxiety and depression scores of the M1 had an effect on pain reduction lasting for up to
over time between the two groups (P > 0.05). Memory score 6 mos. Tekin et al.41 determined improvement in quality of life
was significantly increased in group A at the 6th week com- of patients with FMS as well as effective pain reduction with
pared with the baseline (P = 0.004). In the comparison be- 10-Hz rTMS applied over M1. Lee et al.25 revealed that appli-
tween groups at the 6th week, although there were statistical cation of 10-Hz rTMS to the left M1 may have antidepressive

FIGURE 3. The VAS-pain, VAS-stiffness, and FSS scores according to treatment groups and time. *Statistically significant difference (P < 0.05 level).

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Bilir et al. Volume 100, Number 2, February 2021

FIGURE 4. Fibromyalgia impact questionnaire scores according to treatment groups and time. *Statistically significant difference (P < 0.05 level).

and pain-modulating effects in patients with FM. Unlike these Short et al.46 applied 10-Hz rTMS to the left DLPFC and re-
studies, Boyer et al.45 showed that high-frequency rTMS over vealed that at the 2nd week, there was a statistically significant
the left M1 for 14 sessions over 10 wks had a delayed positive decrease in FIQ scores in the active rTMS group compared
impact on patients’ quality of life without effect on pain. with the sham group, but this decrease could not be detected
Regarding the previous studies of 10-Hz rTMS applied to in the subsequent measurements. Altas et al.15 revealed that
the left DLPFC in FMS, conflicting results have been reported. 10-Hz rTMS (90% RMT, 1200 pulses) to the left DLPFC treat-
Hou et al.10 reported that the DLPFC stimulation may be better ment protocol seems to be promising in improving quality of
in depression improvement and M1 may be better in pain re- life in FMS; however, only one assessment was performed at
duction. Avery et al.26 revealed that a total of 15 sessions of the end of the treatment. Fitzgibbon et al.24 found no signifi-
10-Hz rTMS over the left DLPFC did not show significant im- cant improvement in both 36-item short-form health survey
provement in pain scores. Similarly, Altas et al.15 did not find and FIQ scores with 4 wks of daily rTMS (120% RMT, 3000
any significant pain reduction in active rTMS group compared pulses) to the left DLPFC. Similarly, in this study, a significant
with sham group with high-frequency rTMS to the left DLPFC. improvement in FIQ score of the active group was seen at 2nd
However, Short et al.46 revealed that high-frequency rTMS to week, but changes in FSS over time did not differ between the
the left DLPFC as an adjunct to pharmacotherapy may reduce treatment groups. The differences in sample sizes, population
FMS pain. Fitzgibbon et al.24 also reported a clinically meaning- characteristics, stimulation protocols, and duration of treat-
ful improvement in pain intensity with 10-Hz rTMS over left ments between studies result with variable responses to rTMS
DLPFC. Likewise, in their recent guideline, Lefaucher et al.21
(2020) reported that in FMS, high-frequency rTMS of the left
DLPFC is more efficacious on pain (probable efficacy, level TABLE 3. Comparison of VAS-pain, VAS-stiffness, FIQ, and FSS
B), whereas high-frequency rTMS of the left M1 is more effica- scores according to treatment groups and time
cious on the quality of life (probable efficacy, level B). In this
Baseline 2nd Week 6th Week
study, the left DLPFC was selected as the stimulation site with
the aim of reducing pain. The 10-Hz rTMS over left DLPFC VAS (pain)
for 14 sessions (10 induction sessions daily, 4 maintenance ses- Group A 7.20 ± 1.75 5.30 ± 2.11 5.70 ± 2.63
sions weekly) yielded a reduction in pain scores from baseline in Group B 7.40 ± 1.35 6.80 ± 1.69 6.70 ± 1.83
the active rTMS group; however, this change was not statisti- VAS (stiffness)
cally significant when compared with sham group. Patient’s ex- Group A 7.40 ± 1.58 5.10 ± 2.13 5.40 ± 2.67
pectation of recovery with rTMS treatment and/or close Group B 7.60 ± 1.17 6.60 ± 1.96 5.10 ± 3.51
follow-up by a physician during the treatment period might affect FIQ
the responses even with the sham treatments. Besides from pain, Group A 65.86 ± 8.27 48.35 ± 16.64 51.71 ± 22.17
quality of life, fatigue, stiffness, anxiety-depression, and cognitive Group B 66.44 ± 11.40 54.39 ± 15.47 56.02 ± 22.57
state did not differ between active rTMS and sham groups. FSS
Long-term somatic and psychological symptoms can lead Group A 5.28 ± 1.23 4.77 ± 1.53 4.89 ± 1.59
to impaired health-related quality of life in FMS patients. As Group B 6.08 ± 1.11 5.49 ± 1.50 5.39 ± 1.62
stated previously, Lefaucheur et al.47 recently reported that Values are mean ± SD. The values in bold are significantly different from
high-frequency rTMS of the left M1 has probable efficacy on baseline at the P < 0.05 level.
the quality of life in FMS. There are conflicting results regard- Group A, active TMS; Group B, sham.
ing the effect of rTMS to left DLPFC on quality of life in FMS.

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Volume 100, Number 2, February 2021 rTMS in Fibromyalgia Syndrome

TABLE 4. Comparison of changes in HADS and ACE-R scores over time in the groups

Group A (n = 10) Group B (n = 10)

Baseline 6th Week Baseline 6th Week Pa Pb Pc Pd
HADS 19.30 ± 8.14 18.80 ± 7.82 22.90 ± 5.61 17.60 ± 10.68 0.720 0.192 0.762 0.384
Anxiety 11.40 ± 5.42 11.50 ± 4.35 13.90 ± 3.21 10.30 ± 5.10 0.915 0.045 0.578 0.167
Depression 7.90 ± 3.28 7.30 ± 4.64 9.00 ± 3.27 7.30 ± 4.64 0.546 0.381 >0.99 0.603
ACE-R (total) 62.50 ± 18.80 66.50 ± 19.67 76.90 ± 11.17 81.40 ± 7.79 0.064 0.099 0.046 0.873
MMSE 22.10 ± 5.22 23.50 ± 5.80 27.10 ± 2.56 27.30 ± 2.31 0.089 0.846 0.079 0.345
Attention and 13.5 (9.2–16.5) 15.5 (11.2–17) 17.5 (15–18) 18 (17.7–18) 0.062 0.059 0.003 0.664
orientation
Memory 10.40 ± 3.92 12.90 ± 3.78 13.20 ± 3.71 15.80 ± 3.85 0.004 0.075 0.107 0.946
Verbal fluency 8.20 ± 3.19 7.90 ± 3.03 9.60 ± 3.95 9.60 ± 1.96 0.560 >0.99 0.154 0.770
Language 22 (10.5–25) 21.5 (14.2–23.5) 23.5 (20.7–25.2) 24.5 (21.7–25.2) 0.677 0.242 0.079 0.642
Visual-spatial abilities 13 (11–14.2) 14 (9.75–15.2) 15 (13.7–1) 15.5 (13.7–1) 0.394 >0.99 0.185 0.543
Values are mean ± SD or median (interquartile range). The values in bold are statistically significantly different.
P a, baseline and 6th week comparison within the group A; P b, baseline and 6th week comparison within the group B; P c, 6th week comparison between groups;
d
P , comparison of differences from baseline between the groups.
Group A, active TMS; Group B, sham.

treatments. Relatively shorter treatment periods may prevent total of 11 sessions of 10-Hz rTMS (80% RMT, 1500 pulses)
revealing the exact efficacies of the treatments. were applied to the left M1 region for 11 wks, and no signifi-
Fatigue and stiffness are other symptoms of FMS, which cant cognitive change was reported at the 3rd and 11th weeks.
can complicate the daily activities of patients. Several studies To our knowledge, our study is the first trial that evaluated the
evaluated the effects of rTMS on pain and stiffness in FMS. effect of high-frequency rTMS to the left DLPFC on cognitive
Avery et al.26 assessed 10-Hz rTMS (120% RMT, 3000 pulses, status in FMS. We did not find any significant difference in
15 sessions) to the left DLPFC in the treatment of chronic cognitive evaluation total scores and all subfactors over time,
widespread pain and found significant differences in multidi- but a significant increase was observed in memory scores com-
mensional fatigue inventory scores compared with baseline. pared with the baseline in the active rTMS group. When it
Fitzgibbon et al.24 reported improvements on measures of comes to depression, a definite antidepressant efficacy of the
physical and general fatigue in the active (10-Hz rTMS over high-frequency rTMS to the left DLPFC is well-known.16,21
left DLPFC, 120% RMT, 3000 pulses, 20 sessions) rTMS However, any significant difference in HADS scores with
group compared with the sham group. However, Altas et al.15 high-frequency rTMS to the left DLPFC was not found in this
did not find any significant difference in FSS scores in the favor study. The lack of observing antidepressant effect of the treat-
of 10 Hz (90% RMT, 1200 pulses, 15 sessions) rTMS stimulation ment in this study is probably due to the relatively shorter du-
to the left DLPFC when compared with sham stimulation. Simi- ration of our treatment because studies on depression usually
larly, FSS scores did not differ between the treatment groups in include more number of sessions and more number of pulses
this study. Lefaucheur et al.47 (2017) suggested the stimulation per sessions. Besides, antidepressant medications of the pa-
of M1 area to reduce fatigue. Therefore, targeting M1 may be pre- tients may have also affected the results. Further studies includ-
ferred when fatigue is the prominent symptom. On the other hand, ing larger number of FMS patients for longer treatment periods
stiffness has been evaluated as a part of FIQ in studies on FMS are needed to interpret these results more accurately.
patients. Mhalla et al.29 revealed that 10-Hz rTMS to the M1 There are a number of strengths of this study. First comes
significantly decreased the stiffness subscore of FIQ. By con- from the double-blind, randomized, sham-controlled design.
trast, Passard et al.28 reported no significant improvement in Besides, it is one of the few studies investigating the effects
FIQ-stiffness scores with rTMS (10 Hz, 80% RMT, 2000 of high-frequency neuronavigated rTMS applied to the left
pulses, 10 sessions) to the motor cortex. Although a significant DLPFC in FMS patients. Addition of maintenance sessions af-
improvement in VAS-stiffness scores was found in the active ter induction sessions also increase the strength of this study.
rTMS group at the 2nd week, this improvement was not differ- On the other hand, this study has several limitations. First
ent from the sham group in terms of changes from baseline. of all, unfortunately, there is no sham probe compatible with
Psychiatric disorders, including depression or anxiety, and TMS device used in this study; therefore, sham stimulation
cognitive problems are common in patients with FMS, which was performed with the reversely positioned probe over left
may also influence the physical-social functioning and quality DLPFC by setting stimulus intensity to the 1% of RMT (to en-
of life of the patients. Most of the patients with FMS report sure the clicking sound without actual stimulation of the brain).
concentration difficulties, memory problems, mental confu- Secondly, although there was no difference between the groups
sion, or a combination of these complaints. Baudic et al.22 con- in terms of comorbid diseases and medications at the begin-
ducted the first randomized controlled study in English ning of the study, concomitant medications might have con-
literature that investigated the effects of rTMS on cognitive founded the results. Finally, duration of the treatment was
functions in FMS patients. In the study by Baudic et al.,22 a relatively short- and long-term effects could not be evaluated.

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Bilir et al. Volume 100, Number 2, February 2021

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