Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on Pain, Fatigue, Quality of Life, Cognitive Function and Mood in Fibromyalgia
Phase: NA
Conditions: Fibromyalgia
Sponsor: Izmir Katip Celebi University

1 
Repetitive Transcranial Magnetic Stimulation (rTMS) in Fibromyalgia 
NCT number: NCT03909009 
Date: 14.03.2019 

2 
Objectives 
Fibromyalgia syndrome (FMS) is a chronic pain condition characterized by 
widespread pain, stiffness, overwhelming fatigue, sleep disturbance, alteration in mood, 
cognitive dysfunction (fibrofog) and impaired quality of life and daily function (1,2). 
FMS is present in as much as 0.2% to 6.6% of the general population and is more common 
in women than in men (3). It has substantial impacts on quality of life, physical 
functioning and social-occupational productivity therefore financial costs are an 
economic burden to these patients (4). The pathophysiology of this syndrome is still 
unknown but genetic predisposition, hypothalamic-pituitary-adrenal axis dysfunction, 
environmental factors, autonomous dysfunction, metabolic factors, neuropathies and 
neuromodulation all being considered to be involved in the onset and course of the disease 
(2,5). As we know today, the most acceptable theory is the central sensitization that 
includes altered pain processing based on peripheral and central nervous system 
influences (5,6). 
The purpose of FMS management is to reduce pain, improve sleep and restore 
physical, emotional and mental function, thereby improving overall quality of life but 
there is no gold standard treatment method due to the difficulty of the diagnosis of the 
disease as well as the unknown pathophysiology (2,7). High quality evidence are 
supporting multidisciplinary approach that include nonpharmacological therapies 
(education, exercise, cognitive behavioral therapy, physical-therapy agents, acupuncture, 
multicomponent treatments) and pharmacological therapies (tricyclics, serotonin 
norepinephrine reuptake inhibitors, and gabapentinoids) to achieve optimal management 
results (7-9). Recently, a growing number of studies are performed on modulation of 

3 
central pain pathways of FMS. The promising treatment option in this regard is seen as 
neuromodulation techniques such as transcranial magnetic stimulation (TMS) (10,11). 
Repetitive transcranial magnetic stimulation (rTMS) is a safe and non-invasive 
method of stimulating neurons in the cerebral cortex. It is used to induce changes in brain 
activity that can produce after-effects on the brain (12,13). rTMS modulates cortical 
plasticity, which is called the functional rearrangement of connections between neurons 
and neuronal features (12,13). It is generally assumed that rTMS-induced effects may 
closely relate to synaptic plasticity, such as long-term potentiation (LTP) or depression 
(LTD) (13,14). An after-effect induced by rTMS depends on stimulation frequency. High-
frequency rTMS at 5 Hz or higher transiently increases cortical excitability (i.e. LTP-
like), while stimulation at 1 Hz decreases cortical excitability (LTD-like) (14). rTMS also 
affects brain activities related to pain modulation and processing. Therefore, its use in 
pain syndromes is increasing (15,16). Additionally, rTMS offers potential for clinical 
application in a variety of neurological, psychiatric diseases (e.g. stroke, Parkinson, 
dementia, depression) (16-18). Also recently, the success of these treatments is enhanced 
by using neuronavigation systems that accurately position the coil on a target and keep 
the coil in the correct place during the session (19). 
Although there are many randomized clinical trials and meta-analysis revealing 
beneficial effects of rTMS in FMS, there is no consensus regarding the exact efficacy, 
neither on the optimal parameters of stimulation. Studies have generally focused on high 
frequency stimulation of the left primary motor cortex (M1) or left dorsolateral prefrontal 
cortex (DLPFC). In recent meta-analysis, few randomized controlled, double-blind 
studies were evaluated and these studies mainly investigated pain, quality of life, and 
mood in FMS. Klinck et al., reported that there was no significant difference between 

4 
sham or active rTMS for reducing pain or depression but active rTMS was associated 
with a significant improvement on quality of life (11). Saltychev et al. revealed moderate 
evidence that rTMS is not more effective than sham in reducing the severity of pain in 
FMS (20). Hou et al. suggested that M1 stimulation may be better in pain reduction and 
the DLPFC may be better in depression improvement (10). On contrary to this study, 
recently Lefaucheur et al. reported that high frequency-rTMS of the left DLPFC is more 
efficacious on pain, while high frequency -rTMS of the left M1 is more efficacious on the 
quality of life (21). In addition, there are very few studies investigating the effect of TMS 
treatment on cognitive dysfunction, which is an important problem in FMS (22). It is clear 
that there is still a need for further studies on the exact clinical effects of rTMS treatment 
in FMS. 
Therefore, this study aimed to evaluate the effectiveness of 10 Hz neuronavigated 
rTMS to the left DLPFC on pain, stiffness, fatigue, depression/anxiety, quality of life and 
cognitive functions in FMS. 

5 
Methods 
Participants 
Participants were recruited from Physical Medicine and Rehabilitation (PMR) 
outpatient clinics of a university hospital. Twenty patients (mean ages: 45.25 ± 9.08 years, 
range 29 to 64 years; 20 females) with FMS who met the following inclusion criteria were 
included in the study: (1) adults (age between 18-65 years); (2) diagnosis of FMS 
according to 2016 Fibromyalgia diagnostic criteria; (3) the mean pain intensity is VAS 
≥4 /10; (4) stable treatment for at least last 3 months. Patients were excluded: if they had 
a clinical condition to be contraindicated for TMS (e.g. metallic implant, cardiac pace, 
pregnancy, lactation, epilepsy, head trauma, history of cranial operation); significant 
medical or psychiatric illness including malignancy, major depression, personality 
disorder, history of substance or alcohol abuse; major orthopedic/ neurological problems 
that limit daily life activities; pregnancy/breastfeeding; concomitant inflammatory 
rheumatic diseases, autoimmune diseases or other painful disorders and patients who have 
received TMS treatment before. 
Study design and ethics 
This is a single-center, prospective, randomized, double-blind, sham-controlled 
study in two-arm parallel-group design. Participants were informed about the study and 
provided written informed consents. The protocol was performed in accordance with the 
ethical standards laid down in the 1964 Declaration of Helsinki and approved by the 
local Research Ethics Committee (Approval number: 14.03.2019/25). This study 
was registered on www.clinicaltrials.gov with ID NCT03909009. 

6 
Demographics 
At baseline, demographic information including age, gender, weight, height, body 
mass index (BMI), dominant side, marital status, education level, occupation, disease 
duration, additional diseases, smoking and alcohol use, drugs used for FMS treatment 
were questioned. 
Randomization and blinding 
Randomization was performed using computer-generated block randomization 
with 1:1 allocation between the active rTMS group (Group A) and the sham-control group 
(Group B) by an independent researcher not involved in the rTMS treatment sessions, 
patient selection or clinical evaluations. 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 about the distribution of groups, patient 
selection and interventions. The blind investigator performed patient evaluations at the 
beginning of treatment, at the end of the 2nd and 6th weeks. The patients did not know 
which group they were in during the study. 
Outcome assessment and data collection 
After recording general demographic data clinical assessments were performed. 
All clinical outcome measures were assessed by an experienced researcher who was 
familiarized with the scales and tests used in this study and who was blinded of the group 
assignment. The clinical assessments consisted of six main sections: (1) Pain severity 
(VAS-pain) (2) Stiffness severity (VAS-stiffness) (3) Fibromyalgia Impact Questionnaire 
(FIQ) (4) Fatigue Severity Scale (FSS) (5) Hospital Depression Anxiety Scale (HADS) 
(6) Addenbrook Cognitive Examination - revised version (ACE-R)

7 
Primary clinical outcome measure included VAS-pain (at the end of the 2nd week) 
whereas secondary outcome measures included FIQ and VAS-pain scores at the end of 
the 6th week.  
Visual analog scale: Pain severity and stiffness severity were evaluated with VAS. 
VAS is a psychometric measuring instrument designed to document the severity of 
disease-related symptoms. In this study, the severity of the pain and stiffness 
experienced at rest were assessed on a 10cm VAS (Total score: 0-10)(Higher scores 
mean a worse outcome) (0=no pain/stiffness, 10=severe pain/stiffness) at baseline, at
2nd week and at the end of treatment (6th week) (23). 
Fibromyalgia Impact Questionnaire (FIQ): Functional health status and quality of 
life of the participants were assessed with the FIQ, which measures 10 different features 
(physical functioning, missed days of work, depression, anxiety, feeling good, morning 
tiredness, pain, stiffness, fatigue, and well-being over the past week). The total FIQ 
score is 0-80 points. High scores indicate low functionality level. In our study, FIQ was
evaluated at baseline, at the end of the 2nd and 6th week (24). 
Fatigue Severity Scale (FSS): Severity of fatigue was evaluated with FSS, a 9-
item self-report questionnaire scale. Each item of this scale consists of statements that 
are scored on a seven-point Likert type scale ranging from 1 to 7. Total FSS 
score is calculated as mean value of the nine items. Higher scores indicate higher 
fatigue severity (Total score range: 1-7). FSS was assessed at baseline, at the end of
the 2nd and 6th week (25). 
Hospital Anxiety and Depression Scale (HADS): HADS is an assessment tool 
developed to identify the risk of anxiety and depression and measure its level and change 
of severity. Its subscales are anxiety and depression. It contains 14 questions in total, 
including 7 (odd numbers) measuring anxiety and 7 (even numbers) measuring 

8 
depression.  The lowest and highest total score that a person can obtain from this scale 
are 0 and 42, respectively. High scores are associated with a worse psychiatric 
condition. HADS was evaluated at baseline and 6th week of study (26).
Addenbrook Cognitive Examination Revised (ACE-R): Addenbrook 
Cognitive Examination-Revised is a brief cognitive test that consists of 5 basic sections: 
attention and orientation, memory, verbal fluency, language and visual-spatial abilities. 
Total score that can be obtained is 0-100. Higher scores are associated with a better 
cognitive state. ACE-R is considered useful in discriminating cognitively normal
subjects from patients with mild cognitive impairment. ACE-R was assessed at 
baseline and 6th week of our study (27). 
Interventions 
Twenty patients were randomized into two groups. After randomization, group 
A received total 14 sessions of rTMS, 10 sessions daily (5 days/week, 2 weeks) 
and 4 sessions weekly (1 day/week, 4 weeks). Group B received sham treatment in 
the same sessions and time. 
Neuronavigated repetitive transcranial magnetic stimulation: Brain images 
for participants were performed on a 1.5T magnetic resonance scanner (GE Sigma 
HDxt, General Electric Medical Systems, Milwaukee, WI, USA) using an eight-
channel head coil. Magnetic resonance imaging (MRI) scans of each participant’s brain 
were imported to the 3D guided neuronavigation device (NeNa-Neural navigator, The 
BrainTRAKTM, Brain Science Tools BV, Utrecht, Netherlands). Then, we performed 
brain segmentation and the creation of stimulation target. The location of the left 
DLPFC was determined by an experienced researcher in accordance with the literature 
(28). These information were saved and used to target the left-DLPFC in the future 
sessions. The position of the TMS 

9 
coil and the patient’s head was tracked using the BrainTRAKTM, a magnetic position 
tracking device built into the Neural Navigator. 
A Neuro-MS/D TMS device (Neurosoft, Russia) with a figure-of eight coil was 
used for rTMS. The participants were seated in a comfortable chair with headrest and 
armrests, and were told to rest both hands and upper limbs on top of their thighs. At the 
beginning of each session, the resting motor threshold (RMT) of each participant was 
determined using Neuro-MEP-Micro 2-channel Electromyogram (EMG) (Neurosoft, 
Russia) device. RMT was defined as the minimum stimulation intensity to evoke an MEP 
greater than 50μV in at least 5 of 10 single-pulse TMS trials applied to the left primary 
motor cortex (M1). EMG signals were recorded from electrodes placed over the first 
dorsal interosseous muscle of the right hand, with a circular ground electrode placed over 
the wrist. rTMS therapy was applied under the guide of neuronavigation with the 
following parameters: target-left DLPFC, with the %90 of the RMT, 10 Hz stimulation 
for 5 seconds intervals (on) with 25 seconds inter-train intervals (off), 15 minutes, 1500 
pulses. The stimulation parameters of the study protocol are within the safety limits 
recommended for rTMS (29). For sham stimulation, probe localization was performed as 
in the active group but probe reversely positioned and during sham stimulation, patients 
heard a sound similar to the sound heard by those receiving the active treatment. 
Moreover, all patients were rTMS-naive, so they could not recognize the sham or active 
treatment techniques. 
Sample size 
Sample size calculation was performed with G*Power software (G*Power, version 
3.1.9.2, Germany). A priori sample size based on the work of Tekin et al. (30) was 
calculated on the basis of changes in pain scores (VAS) evaluated before and after the 

10 
treatment. It was determined that at least 5, total 10 patients in each group should be 
included in the study according to 80% power, 5% margin of error and 1.73 effect size. 
Considering the statistical methods and the drop of patients from the study, the sample 
size was planned as at least 10 patients in each group and at least 20 patients in total. 
Statistical analysis 
Database management and statistical analyses were performed by an independent 
researcher. The statistical analysis was performed by SPSS Statistics 22.0 (IBM Corp., 
Armonk, New York, ABD) software. As the descriptive statistics, the number of units 
(n), percent (%), mean ± standard deviation (𝑥̅ ± 𝑠𝑠), median [IQR (interquartile range)] 
values were given. Distributions of continuous variables were evaluated using the 
Shapiro–Wilk test and Q-Q plots. Pearson chi-square test, Fisher’s Exact test, and 
independent samples t-test were performed to determine differences between the 
demographic and clinical characteristic of the groups. Wilcoxon’s signed-rank test and 
Mann-Whitney U-test were used to determine differences within and between the groups’ 
baseline, 2nd or 6th week outcome parameters. If the two groups met the assumptions in 
terms of pain, stiffness, FIQ, and FSS variables measured at three different times, they 
were compared using bidirectional (treatment method x time) variance analysis in 
repeated measurements. The variables examined in the 95% confidence level and P values 
less than 0.05 were considered significant. 

11 
Ethics Committee Approval 
Author declared that the research was conducted according to the principles of the World 
Medical Association Declaration of Helsinki “Ethical Principles for Medical Research 
Involving Human Subjects”, (amended in October 2013). 
University local Research Ethics Committee Approval number: 14.03.2019/25 
Informed Consent 
Written informed consent was obtained from the patients who participated in this study 
Declaration of conflicting interests 
The authors declared no conflicts of interest with respect to the authorship and/or 
publication of this article. 
Funding 
This work was supported by Izmir Katip Çelebi University Scientific Research Project 
fund. 
Acknowledgement 
None 

12 
References 
1. Clauw DJ. Fibromyalgia: a clinical review. JAMA 2014;311:1547-55.
2. Sumpton JE, Moulin DE. Fibromyalgia. Handb Clin Neurol 2014;119:513-27.
3. Marques AP, Santo ASDE, Berssaneti AA, Matsutani LA, Yuan SLK. Prevalence of
fibromyalgia: literature review update. Rev Bras Reumatol Engl Ed 2017;57:356-63.
4. Lacasse A, Bourgault P, Choinière M. Fibromyalgia-related costs and loss of
productivity: a substantial societal burden. BMC Musculoskelet Disord 2016;17:168.
5. Chinn S, Caldwell W, Gritsenko K. Fibromyalgia Pathogenesis and Treatment
Options Update. Curr Pain Headache Rep 2016;20(4):25.
6. Talotta R, Bazzichi L, Di Franco M, Casale R, Batticciotto A, Gerardi MC,et al. One
year in review 2017: fibromyalgia. Clin Exp Rheumatol 2017;35(3):6-12.
7. Macfarlane GJ, Kronisch C, Dean LE, Atzeni F, Häuser W, Fluß E, et al. EULAR
revised recommendations for the management of fibromyalgia. Ann Rheum Dis
2017;76:318-28.
8. Fitzcharles MA, Ste-Marie PA, Goldenberg DL, Pereira JX, Abbey S, Choinière M,
et al. 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia
syndrome: executive summary. Pain Res Manag 2013;18:119-26.
9. Thieme K, Mathys M, Turk DC. Evidenced-Based Guidelines on the Treatment of
Fibromyalgia Patients: Are They Consistent and If Not, Why Not? Have Effective
Psychological Treatments Been Overlooked? J Pain 2017;18:747-56.
10. Hou WH, Wang TY, Kang JH. The effects of add-on non-invasive brain stimulation
in fibromyalgia: a meta-analysis and meta-regression of randomized controlled trials.
Rheumatology (Oxford) 2016;55:1507-17.

13 
11. Knijnik LM, Dussán-Sarria JA, Rozisky JR, Torres IL, Brunoni AR, Fregni F, et al .
Repetitive Transcranial Magnetic Stimulation for Fibromyalgia: Systematic Review
and Meta-Analysis. Pain Pract 2016;16:294-304.
12. Klomjai W, Katz R, Lackmy-Vallée A. Basic principles of transcranial magnetic
stimulation (TMS) and repetitive TMS (rTMS). Ann Phys Rehabil Med 2015;58:208-
213.
13. Hamada M, Rothwell JC. 2016. Neurophysiology of rTMS: Important Caveats When
Interpreting the Results of Therapeutic Interventions. In: Platz T, editor. Therapeutic
rTMS in neurology. Switzerland: Springer International Publishing. pp. 1-11.
14. Simonetta-Moreau M. Non-invasive brain stimulation (NIBS) and motor recovery
after stroke. Ann Phys Rehabil Med 2014;57:530-542.
15. Altas EU, Askin A, Beşiroğlu L, Tosun A. Is high-frequency repetitive transcranial
magnetic stimulation of the left primary motor cortex superior to the stimulation of
the left dorsolateral prefrontal cortex in fibromyalgia syndrome? Somatosens Mot Res
2019;36:56-62.
16. Lefaucheur JP, André-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, et
al. Evidence-based guidelines on the therapeutic use of repetitive transcranial
magnetic stimulation (rTMS). Clin Neurophysiol 2014;125:2150-206.
17. Aşkın A, Tosun A, Demirdal ÜS. Effects of low-frequency repetitive transcranial
magnetic stimulation on upper extremity motor recovery and functional outcomes in
chronic stroke patients: A randomized controlled trial. Somatosens Mot Res
2017;34:102-107.
18. Tosun A, Türe S, Askin A, Yardimci EU, Demirdal SU, Kurt Incesu T,et al. Effects
of low-frequency repetitive transcranial magnetic stimulation and neuromuscular

14 
electrical stimulation on upper extremity motor recovery in the early period after 
stroke: a preliminary study. Top Stroke Rehabil 2017;24:361-7.  
19. Lefaucheur JP. Transcranial magnetic stimulation. Handb Clin Neurol
2019;160:559-580.
20. Saltychev M, Laimi K. Effectiveness of repetitive transcranial magnetic stimulation
in patients with fibromyalgia: a meta-analysis. Int J Rehabil Res 2017;40:11-18.
21. Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, et al.
Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic
stimulation (rTMS): An update (2014-2018). Clin Neurophysiol 2020;131:474-528.
22. Baudic S, Attal N, Mhalla A, Ciampi de Andrade D, Perrot S, Bouhassira D.
Unilateral repetitive transcranial magnetic stimulation of the motor cortex does not
affect cognition in patients with fibromyalgia. J Psychiatr Res 2013;47:72-7.
23. McCormack HM, Horne DJ, Sheather S. Clinical applications of visual analogue
scales: a critical review. Psychol Med 1988;18:1007-19.
24. Burckhardt CS, Clark SR, Bennett RM.The fibromyalgia impact questionnaire:
development and validation. J Rheumatol 1991;18:728-33.
25. Schwartz JE, Jandorf L, Krupp LB. The measurement of fatigue: a new instrument. J
Psychosom Res 1993;37:753-62.
26. Zigmond AS, Snaith PR. The hospital anxiety and depression scale. Acta Psychiatr
Scand 1983;67:361-70.
27. Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR. The Addenbrooke’s
Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia
screening. Int J Geriat Psychiatry 2006;21:1078-85.

15 
28. Pommier B, Vassal F, Boutet C, Jeannin S, Peyron R, Faillenot I. Easy methods to
make the neuronavigated targeting of DLPFC accurate and routinely accessible for
rTMS. Neurophysiol Clin 2017;47:35-46.
29. Rossi S, Hallett M, Rossini PM, Pascual-Leone A; Safety of TMS Consensus Group.
Safety, ethical considerations, and application guidelines for the use of transcranial
magnetic stimulation in clinical practice and research. Clin Neurophysiol
2009;120(12):2008-39.
30. Tekin A, Özdil E, Güleken MD, İlişer R, Bakım B, Öncü J, et al. Efficacy of High
Frequency [10 Hz] Repetitive Transcranial Magnetic Stimulation of the Primary
Motor Cortex in Patients with Fibromyalgia Syndrome: A Randomized, Double
Blind, Sham-Controlled Trial. Journal of Musculoskeletal Pain Mart 2014;22(1):20-
6.