# Effects of Repetitive Transcranial Magnetic Stimulation and Multicomponent Therapy in Patients With Fibromyalgia: A Randomized Controlled Trial

Michel Guinot, Caroline Maindet, Hasan Hodaj, Enkelejda Hodaj, Damien Bachasson, Sébastien Baillieul, Jean-Luc Cracowski, Sandrine Launois

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## To cite this version:

Michel Guinot, Caroline Maindet, Hasan Hodaj, Enkelejda Hodaj, Damien Bachasson, et al. Effects of Repetitive Transcranial Magnetic Stimulation and Multicomponent Therapy in Patients With Fibromyalgia: A Randomized Controlled Trial. Arthritis Care & Research = Arthritis Care and Research, 2021, 73 (3), pp.449-458. 10.1002/acr.24118. hal-04760310

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# Effects of Repetitive Transcranial Magnetic Stimulation and Multicomponent Therapy in Patients With Fibromyalgia: A Randomized Controlled Trial

Michel Guinot,<fnref n="1" /> ID, Caroline Maindet,² Hasan Hodaj,² Enkelejda Hodaj,³ Damien Bachasson,⁴ Sébastien Baillieul,<fnref n="1" /> Jean-Luc Cracowski,³ and Sandrine Launois⁴

**Objective.** Fibromyalgia (FM) is a chronic painful condition partly due to alterations in pain modulation by the central nervous system. Multicomponent therapy (MT) and repetitive transcranial magnetic stimulation (rTMS) have both been reported as pain modulators in patients with FM. The aim of this study was to compare the effects of rTMS on pain with a combination of MT and rTMS versus MT alone.

**Methods.** Thirty-nine FM patients with visual analog scale (VAS) results for pain of ≥40 mm were randomized to active or sham rTMS (high-frequency, primary motor cortex M1) plus 12 weeks of MT (3 sessions per week combining aerobic training, pool-based exercises, and relaxation). Repetitive TMS was started 2 weeks prior to MT and maintained until the end of the program (week 14). Assessments were achieved at baseline, at week 14, and at 6 months (week 40) after completion of the program. The main criterion was pain reduction, as assessed by the weekly mean self-reported level of pain (reported daily). Secondary outcomes were cardiorespiratory fitness (graded maximal exercise test), cardiac autonomic adaptations, and FM impact (using scales for FM impact, depression, sleep efficiency, and pain catastrophizing).

**Results.** The reduction of the weekly mean of pain reported daily did not differ significantly between groups (using repeated measures of analysis of variance [ANOVA]). Two-way ANOVAs showed that pain VAS results, as well as cardiorespiratory fitness, quality of life, depression, and catastrophizing, improved significantly at week 14 and remained stable until week 40. Neither cardiac autonomic adaptations nor sleep efficiency changed significantly.

**Conclusion.** Repetitive TMS did not reduce pain in patients with FM who followed the MT program.

## INTRODUCTION

Fibromyalgia (FM) is a chronic disabling condition characterized by generalized pain, sleep disturbances, and widespread sensory disturbances that predominantly affect women (1–3). Although its pathophysiology remains incompletely understood, sensitization of the central nervous system, and control of pain pathways in particular, is recognized as a key mechanism and explains the diversity of FM symptoms and the difficulties in treating patients with FM (2–5).

Although both pharmacologic and nonpharmacologic interventions follow evidence-based recommendations (6,7), their

clinical relevance or the magnitude of their benefits are questionable or limited (8). Tailored multidisciplinary, nonpharmacologic approaches are now advocated by several research groups and guidelines. More specifically, interventions combining patient education, cognitive behavioral therapy, and/or exercise, in particular, pool-based therapy and aerobic reconditioning, are increasingly being used (3,6–11). These multicomponent therapies (MTs) have been shown to produce substantial improvements in quality of life (QoL) and to have mild-to-moderate effects on FM outcomes (6–8,10,12). These effects cannot be explained merely by improvements in muscular and cardiorespiratory fitness but may also be due to alterations in central pain processing (13–15).

<footnote>ClinicalTrials.gov identifier: NCT01308801.</footnote>

<footnote>Supported by the APICIL Foundation.</footnote>

<footnote n="1">¹Michel Guinot, MD, PhD, Sébastien Baillieul, MD: Grenoble Alpes University Hospital, Sports Pathologies Medical Unit, and INSERM U1042, HP2 Laboratory, Grenoble, France; ²Caroline Maindet, MD, Hasan Hodaj, MD: Grenoble Alpes University Hospital, Center for Pain, Grenoble, France; ³Enkelejda Hodaj, MD, Jean-Luc Cracowski, MD, PhD: Grenoble Alpes University Hospital, Clinical Research Center, INSERM CIC1406, Grenoble, France; ⁴Damien Bachasson, PhD, Sandrine Launois, MD, PhD:</footnote>

<footnote>INSERM U1042, Grenoble Alpes University, HP2 Laboratory, Grenoble, France.</footnote>

<footnote>Drs. Guinot and Maindet contributed equally to this work.</footnote>

<footnote>No potential conflicts of interest relevant to this article were reported.</footnote>

<footnote>Address correspondence to Michel Guinot, MD, PhD, Sports and Pathologies Unit, Hôpital Sud, Avenue de Kimberley, F 38130 Echirolles, France. Email: MGuinot@chu-grenoble.fr.</footnote>

<footnote>Submitted for publication April 2, 2019; accepted in revised form November 26, 2019.</footnote>
SIGNIFICANCE & INNOVATIONS

* Repetitive transcranial magnetic stimulation (rTMS) does not reduce pain in patients with fibromyalgia (FM) who undergo multicomponent therapy (MT).

* MT alone seems sufficient to modulate pain and to improve quality of life and secondary outcomes in patients with FM.

* Neither MT nor rTMS improved cardiac autonomic system adaptations in patients with FM.

Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, has been used for various neurologic and psychiatric conditions and is approved for the treatment of depression (16-18). In particular, rTMS modulates the excitability of cortical and deep brain areas through an electromagnetic field applied on the scalp (17). In FM patients, it has been suggested that rTMS produces analgesic effects through the modulation of descending pain pathways (19,20) and of the right limbic area involved in the socioemotional dimension of pain (21). Recent meta-analyses showed that rTMS significantly reduced pain in patients with chronic pain syndrome or FM (20,22). Moreover, pain reduction was greater when primary motor (M1) rather than prefrontal cortex stimulation was applied (20). Nevertheless, this improvement (12%) was lower than the minimum clinically important difference threshold (20,22).

Since both rTMS and MT (exercise in particular) are reported to partly exert pain attenuation through neuroplastic alterations (13,17), we hypothesized that their combination may lead to additional clinically relevant pain reduction. We further hypothesized that rTMS could also improve cardiovascular and hormonal adaptations during exercise in patients with FM through beneficial action on the autonomic nervous system (23). We thus designed a double-blind randomized controlled study to

investigate the effects of active rTMS (ArTMS) versus sham rTMS (SrTMS) applied over the M1 cortex and combined with MT using a visual analog scale (VAS) score for pain at 30 days as the primary outcome.

PATIENTS AND METHODS

**Eligibility criteria.** This study was conducted in the Pain and Rheumatology departments and the Sports Pathologies medical unit of Grenoble Alpes University Hospital. In total, 450 consecutive patients who were secondary- or tertiary-care outpatients were recruited from the pain or rheumatology centers. Patients' eligibility criteria were checked during monthly multidisciplinary meetings.

Inclusion criteria were as follows: 1) diagnosis of FM (using American College of Rheumatology criteria [1]); 2) VAS pain score of ≥40 mm (24); 3) patients naive for rTMS; 4) >18 years of age; and 5) no antidepressants, pain killers, corticosteroids, or nonsteroidal antiinflammatory drugs added 3 months before screening.

Exclusion criteria were as follows: 1) FM associated with chronic inflammatory or autoimmune disease; 2) neuromuscular disease; 3) a severe psychiatric condition (posttraumatic stress syndrome [using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition] or depression); 4) patients unable to exercise on a cycle ergometer, those having cardiac or pulmonary disease, or those having undergone physical reconditioning within 2 years prior to enrollment; 5) a body mass index of >35 kg · meter⁻²; 6) contraindication to rTMS, including a history of seizures; 7) patients with restless legs syndrome or sleep apnea syndrome; 8) pregnant women or those who were breastfeeding; and 9) patients living too far from the hospital (driving time >45 minutes).

**Ethics.** This study conformed to the Declaration of Helsinki and was approved by the local ethics committee (CPP Sud-Est V, IRB 6705) and the French Drug and Device Regulation Agency (EudraCT database no. 20010-A00865-34). All patients

<table><caption>**Figure 1.** Diagram of the treatment course. rTMS = repetitive transcranial magnetic stimulation; VAS = visual analog scale (pain).</caption><thead><tr><th>Time frame</th><th>Week -1 to Week 0</th><th>Week1</th><th>Week2</th><th>Week 3</th><th>Week 4</th><th>Week 5 and 6</th><th>Week 7 to 9</th><th>Week 10 to 14</th><th>Week 15 //</th><th>Week 40</th></tr></thead><tbody><tr><td rowspan="3">Treatments</td><td rowspan="2">Inclusion and allocation treatment</td><td colspan="2">Induction phase of rTMS</td><td colspan="5">Maintenance phase of rTMS</td><td>Post intervention phase</td></tr><tr><td>5 sessions</td><td>5 sessions</td><td>2 sessions</td><td>1 session</td><td>1 session</td><td>1 session</td><td>1 session</td></tr><tr><td>Active rTMS</td><td>5 sessions</td><td>5 sessions</td><td>2 sessions</td><td>1 session</td><td>1 session</td><td>1 session</td><td>1 session</td><td></td></tr><tr><td colspan="11" style="text-align: center; font-weight: bold;">Multicomponent therapy</td></tr><tr><td colspan="11" style="text-align: left; font-size: smaller;">Aerobic training + pool based therapy + relaxation: 3 sessions a week each<br/>Educational therapy: 1-hour monthly session</td></tr><tr><td>Outcomes assessments</td><td>x</td><td colspan="2"></td><td colspan="5"></td><td>x</td><td>x</td></tr><tr><td>Mean weekly pain VAS</td><td>x</td><td>x</td><td>x</td><td>x</td><td>x</td><td>x</td><td>x</td><td>x</td><td>x</td><td>x</td></tr></tbody></table>
gave written informed consent. The study was registered on the
ClinicalTrials.gov website under identifier NCT01308801.

**Study design.** Study design is shown in Figure 1. This was a prospective, randomized, controlled, double-blind and monocentric study. Patients were randomly assigned to either ArTMS or SrTMS. Repetitive TMS started 2 weeks before and lasted throughout the MT program (Figure 1). Randomization was performed from a computer-generated list so that all investigators (excepting the rTMS operator) and physical therapists were unaware of the allocated arm. Randomization was stratified according to mean pain intensity over the 3 days before the time of inclusion (VAS score <70 mm versus VAS score ≥70 mm).

**rTMS protocol.** The rTMS protocol comprised a 2-week induction phase (5 sessions per week) (25), followed by a 12-week, gradually decreasing maintenance phase, 2 sessions for week 3 (the first week of exercise training), and then 1 session per week for weeks 4, 6, 9, and 13, as previously described (19). Repetitive TMS was performed using a MagPro device (MagVenture,

Alpine Biomed). One session delivered 2,000 impulsions at 10 Hz for 20 minutes on the M1 cortex (dominant thenar area). The intensity was set at 80% of the resting motor threshold (RMT) as determined prior to the first session by measuring motor evoked potentials with a monitor linked to the rTMS device (26). A navigation-assisted TMS Navigator stimulation device (Localite) was used to precisely and individually determine the position of the coil based on the patients' anatomic magnetic resonance imaging data set. Sham stimulations were carried out with a sham coil of identical size, color, and shape that emitted the same sound as the active coil.

**MT program.** Patients attended a 12-week multicomponent program comprised of 3 sessions weekly (weeks 3 to 14) (Figure 1). Sessions were performed in groups of 5 patients at the Institut de rééducation de rhumatologie. Each session started with 45-minute aerobic training on an ergicycle, and then 45 minutes of pool-based exercises followed by 45 minutes of relaxation supervised by a physical therapist. Moreover, 3 individual sessions (1 hour per month) of educational

<figure><img src="image_4.png" /><figcaption>**Figure 2.** Flow chart of selected patients with fibromyalgia (FM). rTMS = repetitive transcranial magnetic stimulation; VAS = visual analog scale (pain).</figcaption></figure>
therapy aimed at practicing physical activity were provided by a trained physical therapist. Training was performed on an ergocycle, and the first session comprised three 10-minute stints of continuous exercise at the target intensity (see below), interspersed by 5 minutes of active recovery (free push-pull). The duration of stints was progressively increased every week according to the patient's tolerance, for up to 45 minutes at the target intensity. The target intensity was determined at inclusion and defined as the heart rate (HR) at the first lactate threshold (LT1) assessed during an incremental cardio-pulmonary exercise test (CPET). This intensity is considered sufficient to produce a significant improvement in fitness (27). HR was continuously monitored during the session to control exercise intensity. Pool-based exercises included progressive and tailored balance and posture work groups while sitting or standing. Relaxation was based on sophronization aimed at its use in daily life activities.

**Evaluation of outcomes.** Evaluation was performed by a physician (MG) at baseline (week 0 [W0]), immediately after patients completed the program (W14), and at 6 months (W40) (Figure 1). The primary end point was the difference in VAS pain between baseline and W14. Pain, assessed using the mean of daily values from a self-reported VAS over 7 days, was recorded weekly (24). Secondary end points were FM-related outcomes, cardiorespiratory fitness, and cardiac autonomic nervous system adaptations. FM-related outcomes were assessed using self-administered questionnaires. The functional impact of FM was assessed using the French version of the Fibromyalgia Impact Questionnaire (FIQ) (range 0–100) (28). Depression was assessed using the Beck Depression Inventory (BDI) (range 0–63) (29). The subjective quality of sleep was measured using the Pittsburgh Sleep Quality Inventory (PSQI; range 0–21) (30). Pain catastrophism was evaluated using the Pain Catastrophism Scale (PCS; range 0–52) (31). Response to training was assessed using the Patient Global Improvement of Change (PGIC) and a 7-point Likert scale, with scores of <3 indicating a good response to interventions (32).

**Cardiac autonomic nervous system adaptations.** A head-up tilt test was completed before every CPET (between 2:00 PM and 2:30 PM). Patients were asked to avoid smoking, alcohol, and food consumption at least 2 hours before the test. HR and blood pressure (BP) were continuously monitored for 10 minutes with the patient in supine position, and for 10 minutes with the patient in a standing position (70°). BP was measured with a fingertip photo-plethysmograph, and HR was measured using a 4-lead electrocardiogram (Nexfin). R-R intervals and pulse wave signals were extracted and analyzed according to international recommendations (33) using free Kubios heart rate variability (HRV) analysis software, version 2.0 (University of Kuopio). The temporal parameters (mean HR, mean systolic BP, diastolic and mean BP, and the root mean square of successive differences [RMSSD] of

<table><caption>**Table 1.** Patient characteristics at baseline*</caption><thead><tr><th></th><th>ArTMS<br>(n = 18)</th><th>SrTMS<br>(n = 19)</th></tr></thead><tbody><tr><td>Female, no. (%)</td><td>18 (100)</td><td>15 (79)</td></tr><tr><td>Age, years</td><td>46.5 ± 10.4</td><td>42.8 ± 8.8</td></tr><tr><td>BMI, kg · meter<sup>-2</sup></td><td>26.7 ± 4.8</td><td>25.1 ± 4.5</td></tr><tr><td>Employment, no. (%)</td><td>8 (44.4)</td><td>12 (63.2)</td></tr><tr><td>Education level, no. (%)</td><td></td><td></td></tr><tr><td>College</td><td>9 (50.0)</td><td>12 (63.2)</td></tr><tr><td>High school</td><td>9 (50.0)</td><td>7 (36.8)</td></tr><tr><td>FM characteristics</td><td></td><td></td></tr><tr><td>Symptom duration, years</td><td>11.2 ± 10.9</td><td>9.2 ± 9.6</td></tr><tr><td>Pain VAS score, mm</td><td>60.9 ± 14.9</td><td>57.3 ± 16.1</td></tr><tr><td>FIQ score (of 100)</td><td>65.4 ± 11.8</td><td>64.0 ± 9.4</td></tr><tr><td>BDI score (of 63)</td><td>25.6 ± 11.2</td><td>23.5 ± 11.1</td></tr><tr><td>PCS score (of 52)</td><td>25.4 ± 11.2</td><td>23.7 ± 13.0</td></tr><tr><td>PSQI score (of 21)</td><td>13.9 ± 4.0</td><td>12.2 ± 3.5</td></tr><tr><td>Treatments, no. (%)</td><td></td><td></td></tr><tr><td>Analgesics, level I</td><td>12 (66.7)</td><td>11 (57.9)</td></tr><tr><td>Analgesics, level II</td><td>12 (66.7)</td><td>12 (63.2)</td></tr><tr><td>Analgesics, level III</td><td>1 (5.6)</td><td>1 (5.3)</td></tr><tr><td>Antidepressants</td><td>8 (44.4)</td><td>9 (47.4)</td></tr><tr><td>Benzodiazepines</td><td>1 (5.6)</td><td>2 (10.5)</td></tr><tr><td>NSAIDs</td><td>1 (5.6)</td><td>2 (10.5)</td></tr><tr><td>Others</td><td>10 (55.6)</td><td>6 (31.6)</td></tr><tr><td>Peak exercise values</td><td></td><td></td></tr><tr><td>VO<sub>2</sub>, ml · minute<sup>-1</sup> · kilogram<sup>-1</sup></td><td>17.5 ± 3.1‡</td><td>22.9 ± 6.4</td></tr><tr><td>Predicted VO<sub>2max</sub> %</td><td>72.8 ± 14.9</td><td>82.2 ± 22.4</td></tr><tr><td>HR, beats per minute</td><td>162 ± 23</td><td>159 ± 16</td></tr><tr><td>Blood lactate, mmoles · liter<sup>-1</sup></td><td>7.09 ± 2.10</td><td>7.61 ± 2.49</td></tr><tr><td>Submaximal (LT1) exercise values</td><td></td><td></td></tr><tr><td>VO<sub>2</sub>, ml · minute<sup>-1</sup> · kilogram<sup>-1</sup></td><td>12.0 ± 1.9</td><td>13.3 ± 3.0</td></tr><tr><td>% VO<sub>2peak</sub></td><td>70.1 ± 13.5†</td><td>60.0 ± 10.7</td></tr><tr><td>HR, beats per minute</td><td>130 ± 15‡</td><td>117 ± 12</td></tr><tr><td>Lactate, mmoles · liter<sup>-1</sup></td><td>2.47 ± 0.75</td><td>2.27 ± 0.51</td></tr><tr><td>Supine cardiac autonomic values</td><td></td><td></td></tr><tr><td>HR, beats per minute</td><td>80.6 ± 11.2</td><td>74.8 ± 9.5</td></tr><tr><td>Systolic BP, mm Hg</td><td>117 ± 20</td><td>116 ± 17</td></tr><tr><td>Diastolic BP, mm Hg</td><td>67 ± 12</td><td>64 ± 11</td></tr><tr><td>RMSSD, msec</td><td>20.6 ± 9.3†</td><td>32.4 ± 20.8</td></tr><tr><td>LF<sub>HR</sub>, normalized units</td><td>59.2 ± 13.4†</td><td>49.7 ± 13.9</td></tr><tr><td>HF<sub>HR</sub>, normalized units</td><td>40.9 ± 13.5†</td><td>50.3 ± 13.9</td></tr><tr><td>LF<sub>BP</sub>, mm Hg<sup>2</sup></td><td>12.2 ± 9.7</td><td>13.2 ± 15.8</td></tr><tr><td>BRS index, msec · mm Hg<sup>-1</sup></td><td>5.45 ± 3.23</td><td>8.78 ± 7.15</td></tr></tbody></table>

* Values are the means ± SD unless indicated otherwise. ArTMS = active repetitive transcranial magnetic stimulation; BDI = Beck Depression Inventory; BMI = body mass index; BP = blood pressure; BRS = baroreflex sensitivity; FIQ: Fibromyalgia Impact Questionnaire; FM = fibromyalgia; HF = high frequency; HR = heart rate; LF = low frequency; LT1 = first lactate threshold; NSAIDs = nonsteroidal antiinflammatory drugs; PCS = Pain Catastrophizing Scale; PSQI = Pittsburgh Sleep Quality Inventory; RMSSD = root mean square of successive differences; SrTMS = sham repetitive transcranial magnetic stimulation; VAS = visual analog scale; VO<sub>2</sub> = oxygen consumption. † ArTMS versus SrTMS significantly different at *P* < 0.05. ‡ ArTMS versus SrTMS significantly different at *P* < 0.01.

R-R [34]) and spectral parameters (normalized units of low-frequency [LF<sub>R-R</sub>] and high-frequency density [HF<sub>R-R</sub>], and total power spectral density [PSD<sub>R-R</sub>]) of R-R intervals were retained for analysis. The baroreflex sensitivity index ($\alpha_{LF}$) was calculated as follows (35):

$$ \alpha_{LF} = \sqrt{\frac{\text{LF}_{R-R}}{\text{LF}_{BP}}} $$
**CPET.** A CPET was performed on an Ergoselect 150P cycle ergometer (Ergoline). Power output was increased every 2 minutes until exhaustion or the appearance of intolerable symptoms according to the exercise limitations of FM patients. HR and gas exchanges were continuously monitored using a 12-lead electrocardiogram and an automated Ergocard ergospirometer (Medisoft), allowing the measurement of oxygen uptake (VO₂), carbon dioxide output, and ventilation. Lactate kinetics were measured by sampling a fingertip drop of blood (0.7 µl) during the last 30 seconds of each 2-minute incremental stage of the CPET, and at 2 and 4 minutes of the recovery phase. Blood lactate was measured with a hand-held Lactate Plus lactate oxidase biosensor (Nova Biomedical). LT1 was determined based on a graphical method, as recommended (36). In order to assess exercise tolerance, predicted values of VO₂max were calculated using a validated formula based on activity and age- and sex-matched data (37).

**Statistical analysis.** Main criterion. The primary end point was the difference in the magnitude of the diminution of weekly self-reported pain intensity levels between groups (ArTMS versus SrTMS). In a previous study, significant changes had been found in pain evolution between ArTMS and SrTMS (25). These results were used in the computation of sample size. Eighteen patients were necessary in each treatment group to detect a difference of 20 mm on a 100-mm VAS between weeks 0 and 14, with a power of 80% and an α risk of 5% (using nQuery Advisor, version 7.0 [Statistical Solutions]). With a dropout rate estimated at 20%, 20 patients needed to be included in each group.

Mean daily pain evolution was analyzed over 2 periods: first, the treatment period (weeks 0 to 14) comparing absolute difference from baseline; and secondly, between weeks 14 and 40 to assess the continuity of any effect. Changes were compared using a bilateral Student's t-test when variables followed a normal distribution. Otherwise, a nonparametric Mann-Whitney U test was used. The integrated change in pain from baseline was analyzed with an analysis of covariance, with group and pain at week 0 as covariates. A 2-way analysis of variance (ANOVA) with repeated measures was also performed to investigate a potential group effect (ArTMS versus SrTMS), time effect (weeks 0, 14, and 40), and time × group interaction. Pain analyses were performed on a modified intent-to-treat basis for all randomized patients who had a baseline measurement and received at least 1 session of ArTMS. We used multivariate imputation by chained equations to replace missing data.

**Secondary criteria.** The same analyses were performed to compare the effects of rTMS on secondary outcomes (using the FIQ, BDI, PSQI, and PCS) and on physiologic parameters (using CPET and autonomic nervous system parameters, as previously detailed). A log transformation was completed to normalize autonomic nervous system variables (LF<sub>R-R</sub>, HF<sub>R-R</sub>, PSD<sub>R-R</sub>, and LF<sub>BP</sub>). P values less than 0.05 were considered significant. Statistical analyses were performed using Stata software, version 13.1.

The plan for the statistical analysis was developed in collaboration with the Grenoble Clinical Research Center (CIC 1406).

## RESULTS

**Participants.** A total of 39 patients with FM were randomized, 19 to the SrTMS group, and 20 to the ArTMS group (Figure 2). Two patients were excluded from the active group because inclusion criteria were not fulfilled. One had a VAS pain score of <40 mm. One additional patient (in the ArTMS group) was excluded from analysis for the main criterion because pain VAS data were not available during the entire study. Finally, data from 36 patients were analyzed using a modified intent-to-treat analysis for the main criterion, and data from 37 patients were analyzed for the other variables. Baseline results are shown in Table 1. All patients completed the initiation phase of rTMS, but 5 withdrew during the MT program (2 in the SrTMS group, 3 in the ArTMS group), and 1 was lost to follow-up before week 40 (in the ArTMS group). The reasons for discontinuation were pregnancy (n = 1), moving (n = 1), worsening of FM (n = 1), and personal reasons (n = 2). No adverse effects were recorded during the phases of the study.

**Effects on pain and secondary FM outcomes.** Effects on pain and secondary FM outcomes are shown in Figure 3 and Table 2, respectively. There was neither time × group interaction for VAS pain nor for the FIQ, BDI, PCS, and PSQI scores. Taking into account the characteristics of the study sample, 52 patients would have been required in each group to show a significant time × treatment interaction on pain VAS (with an α risk of 0.05 and a power of 80%). The power of this study was 32%, and the effect size 0.24.

There was no group effect on VAS pain or on FIQ, BDI, PCS, and PSQI scores. There was a time effect in both groups on VAS pain (*P* < 0.05) and on results from the FIQ (*P* < 0.001), the BDI (*P* < 0.001), the Hospital Anxiety and Depression Scale (*P* < 0.05), and the PCS (*P* < 0.05) at W14 versus W0, which persisted until W40. Neither a group nor a time effect was shown for results from the PSQI.

**Effects on the cardiorespiratory system.** Effects on the cardiorespiratory system are shown in Table 2. The ArTMS group displayed smaller improvements in cardiorespiratory fitness than the SrTMS group regarding specific VO₂ at both maximal and submaximal exercise levels (*P* < 0.01). This difference disappeared when VO₂ was expressed according to its predicted (pred) value (*P* = 0.123). There was no significant group effect for lactate and HR<sub>max</sub>.

Cardiorespiratory fitness significantly improved in both groups at maximal and submaximal levels. As for VO₂max, VO₂LT1 significantly increased between baseline and the end of MT (*P* < 0.005 and *P* < 0.0001, respectively). This effect persisted at W40. There was no time × group interaction for VO₂max, VO₂maxpred, or VO₂LT1.
<figure><img src="image_5.png" /><figcaption>**Figure 3.** Mean weekly pain evolution. A, 14 weeks during the repetitive transcranial magnetic stimulation (rTMS) and reconditioning program. A 2-way analysis of variance showed a time effect (a) at week 14 versus week 0 in both groups (*P* < 0.05) but neither a group interaction nor a time × group interaction. B, 26 weeks after rTMS and the training program. ArTMS = active repetitive TMS; SrTMS = sham repetitive TMS; W = week. Bars show the mean ± SD.</figcaption></figure>

**Effects on the cardiac autonomic nervous system.**

There were neither time × group nor time interactions between both resting (Table 3) and head-up tilt test or cardiac autonomic parameters. Supine HR, RMSSD, and HF normalized unit (HFnu) were significantly reduced in the SrTMS group (*P* < 0.05, *P* < 0.01, and *P* < 0.01, respectively) compared to the ArTMS group at baseline and at W14. The RMSSD only differed significantly at W40. Supine LF normalized unit (LFnu) was significantly higher in the SrTMS group than in the ArTMS group at baseline and W14.

**DISCUSSION**

This randomized sham-controlled study showed that ArTMS had no additional effects on self-reported pain in patients with severe FM (32) over and above the effect of the exercise training program being followed. Pain intensity decreased in both groups during the 14-week intervention phase, and this reduction was maintained 6 months after the end of the intervention (Figure 3).

Previous systematic reviews of the literature (20,22,38) have shown that rTMS significantly reduced pain in FM or in chronic pain syndrome, while another study reported a significant effect only on QoL (39). We have provided an updated meta-analysis (data not shown) showing that ArTMS had no superior effect on VAS pain at 30 days compared to SrTMS. The discrepancies concerning the analgesic effect of rTMS in FM could be due to modalities (high- versus low-frequency), locations used in these studies, or the treatment courses of rTMS, while an operator effect cannot be excluded (20). Although there is no recommendation for FM (17), the intensity of magnetic stimulations was set at 80% of the RMT, as previously published in similar studies of FM patients (19,25) and patients with chronic pain (17). Indeed, intensities at 80% or 90% of the RMT are usually used on the motor cortex for patients with chronic pain (see review in ref. 17). The reason for this subliminal intensity was to generate cortical excitation without muscular contractions and to reduce the risk of seizure. Actually, higher intensities are used (110% or 120% of the RMT) when the dorso-lateral prefrontal cortex is stimulated, in particular in depression and sometimes in chronic pain syndromes (17).
<table><caption>**Table 2.** Evolution of fibromyalgia secondary outcomes and graded maximal exercise test values*</caption><thead><tr><th rowspan="2"></th><th colspan="3">ArTMS</th><th colspan="3">SrTMS</th></tr><tr><th>W0</th><th>W14</th><th>W40</th><th>W0</th><th>W14</th><th>W40</th></tr></thead><tbody><tr><td>FIQ score (of 100)†</td><td>64.3 ± 12.0</td><td>53.3 ± 17.9</td><td>52.8 ± 12.8</td><td>62.9 ± 9.9</td><td>51.6 ± 18.7</td><td>51.1 ± 17.2</td></tr><tr><td>BDI score (of 63)†</td><td>25.4 ± 10.5</td><td>18.3 ± 10.3</td><td>20.5 ± 5.8</td><td>23.5 ± 10.8</td><td>17.5 ± 8.5</td><td>17.2 ± 10.0</td></tr><tr><td>PSQI score (of 21)</td><td>13.3 ± 2.7</td><td>11.5 ± 3.5</td><td>12.5 ± 2.9</td><td>12.2 ± 3.5</td><td>13.2 ± 6.5</td><td>11.1 ± 3.5</td></tr><tr><td>PCS score (of 52)†</td><td>25.9 ± 11.0</td><td>17.4 ± 10.8</td><td>18.8 ± 10.8</td><td>23.7 ± 13.0</td><td>20.9 ± 12.0</td><td>20.8 ± 13.2</td></tr><tr><td>PGIC score &lt;3, no. (%)</td><td>NA</td><td>8 (44)</td><td>6 (32)</td><td>NA</td><td>7 (39)</td><td>3 (16)</td></tr><tr><td colspan="7">Graded maximal exercise test</td></tr><tr><td>VO<sub>2max</sub> ml·minute<sup>-1</sup>·kilogram<sup>-1</sup>‡</td><td>17.5 ± 3.0</td><td>20.6 ± 4.0</td><td>20.9 ± 3.5</td><td>22.9 ± 6.2</td><td>24.2 ± 5.4</td><td>23.9 ± 4.4</td></tr><tr><td>%Pred VO<sub>2max</sub>†</td><td>73.5 ± 13.9</td><td>86.3 ± 17.4</td><td>86.2 ± 21.9</td><td>83.3 ± 22.4</td><td>88.0 ± 20.9</td><td>86.5 ± 18.6</td></tr><tr><td>HR<sub>max</sub>, beats per minute</td><td>162 ± 22</td><td>167 ± 17</td><td>170 ± 14</td><td>159 ± 16</td><td>157 ± 18</td><td>162 ± 12</td></tr><tr><td>La<sub>max</sub>, mmoles·liter<sup>-1</sup></td><td>7.09 ± 2.04</td><td>7.70 ± 2.59</td><td>7.27 ± 1.71</td><td>7.61 ± 2.42</td><td>7.55 ± 2.99</td><td>8.62 ± 2.28</td></tr><tr><td>VO<sub>2LT1</sub>, ml·minute<sup>-1</sup>·kilogram<sup>-1</sup>†</td><td>12.0 ± 1.8</td><td>13.6 ± 1.8</td><td>13.7 ± 3.1</td><td>13.3 ± 3.1</td><td>15.4 ± 4.0¶</td><td>14.0 ± 3.3§</td></tr><tr><td>HR<sub>LT1</sub>, beats per minute#</td><td>130 ± 15</td><td>130 ± 16</td><td>133 ± 19</td><td>117 ± 12**</td><td>117 ± 12**</td><td>115 ± 13**</td></tr><tr><td>%VO<sub>2max</sub></td><td>70.1 ± 13.1</td><td>68.3 ± 13.7</td><td>65.8 ± 11.0</td><td>59.6 ± 11.1</td><td>64.2 ± 12.9</td><td>58.6 ± 8.5</td></tr></tbody></table>

* Values are the means ± SD unless indicated otherwise. Two-way analysis of variance with repeated measures showed no group × time interactions. BDI = Beck Depression Inventory; FIQ = Fibromyalgia Impact Questionnaire; HR = heart rate; La = blood lactate; LT1 = first lactate threshold; Max = peak exercise; NA = not available; PCS = Pain Catastrophizing Scale; PGIC = personal global improvement of change; Pred = predicted; PSQI = Pittsburgh Sleep Quality Inventory; VO₂ = oxygen consumption; W0 = week 0 (baseline).

† Time effect: *P* < 0.001.

‡ Time effect: *P* < 0.001; group effect (ArTMS vs. SrTMS): *P* < 0.05 and *P* < 0.01.

§ W14 and W40 differed significantly from baseline (*P* < 0.05).

¶ W14 and W40 differed significantly from baseline (*P* < 0.01).

# Group effect (ArTMS vs. SrTMS): *P* < 0.01.

** SrTMS differed significantly from ArTMS (*P* < 0.01).

The present rTMS protocol reproduced the protocol of Mhalla et al (19), with high-frequency stimulation on the M1 cortex, which seems to be more efficient than prefrontal cortex stimulation (20). It is also possible that of the analgesic effect of rTMS was concealed because the induction phase of our study might not have lasted long enough. Indeed, 4 to 6 weeks (a 5-week session) are recommended for depression, while antidepressant effects of rTMS usually appear as soon as 2 or 3 weeks (18). Nevertheless, in most of these studies, pain improvement did not reach the minimum clinically significant change (15%) (20,22), suggesting that rTMS had low efficiency in FM pain modulation. Our study thus suggests that MT was

the main pain modulator, although it was not designed to assess the superiority of MT versus rTMS. In particular, pain intensity did not decrease during the 2-week initiation phase of rTMS, but only after the beginning of MT (Figure 3). Taken together, these results suggest MT-induced effects on pain, QoL, depression, and cardiorespiratory fitness, as previously reported (8,10), with no additive effect of rTMS.

In regard to the effects on cardiorespiratory fitness and secondary outcomes in FM, a 2-way ANOVA with repeated measures showed that there was a significant improvement in cardiorespiratory fitness in both groups between baseline and the end of the program. Interestingly, this effect persisted 6 months after

<table><caption>**Table 3.** Evolution of resting heart rate (HR) and blood pressure variability*</caption><thead><tr><th rowspan="2"></th><th colspan="3">ArTMS</th><th colspan="3">SrTMS</th></tr><tr><th>W0</th><th>W14</th><th>W40</th><th>W0</th><th>W14</th><th>W40</th></tr></thead><tbody><tr><td>HR sup, beats per minute†</td><td>81 ± 12</td><td>80 ± 12</td><td>83 ± 13</td><td>75 ± 9</td><td>73 ± 10</td><td>75 ± 11</td></tr><tr><td>Delta HR, beats per minute</td><td>17 ± 9</td><td>15 ± 8</td><td>13 ± 5</td><td>13 ± 9</td><td>14 ± 7</td><td>13 ± 8</td></tr><tr><td>MBP sup, mm Hg</td><td>87 ± 15</td><td>86 ± 11</td><td>86 ± 18</td><td>85 ± 13</td><td>88 ± 15</td><td>83 ± 14</td></tr><tr><td>MBP st, mm Hg</td><td>95 ± 15</td><td>95 ± 13</td><td>101 ± 26</td><td>93 ± 12</td><td>95 ± 15</td><td>93 ± 10</td></tr><tr><td>RMSSD sup, msec‡</td><td>20.6 ± 9.6</td><td>22.7 ± 12.0</td><td>20.0 ± 9.9</td><td>32.4 ± 20.7</td><td>36.6 ± 20.7</td><td>33.2 ± 17.5</td></tr><tr><td>LF sup, normalized units†</td><td>59.2 ± 13.0</td><td>65.0 ± 13.8</td><td>65.9 ± 12.6</td><td>49.7 ± 13.5</td><td>47.3 ± 12.9</td><td>56.0 ± 14.9</td></tr><tr><td>HF sup, normalized units§</td><td>40.9 ± 13.1</td><td>35.3 ± 13.7</td><td>34.1 ± 12.6</td><td>50.3 ± 13.5</td><td>52.7 ± 12.9</td><td>43.4 ± 15.7</td></tr><tr><td>LF<sub>SBP</sub> sup, mm Hg<sup>2</sup></td><td>11.6 ± 9.3</td><td>7.8 ± 6.0</td><td>14.5 ± 22.7</td><td>13.2 ± 15.4</td><td>12.1 ± 10.5</td><td>12.3 ± 8.4</td></tr><tr><td>BRS index sup, ms·mm Hg<sup>-1</sup></td><td>5.33 ± 3.06</td><td>7.32 ± 3.42</td><td>6.72 ± 3.90</td><td>8.78 ± 6.96</td><td>7.79 ± 5.32</td><td>8.19 ± 9.27</td></tr></tbody></table>

* Values are the means ± SD. Two-way analysis of variance with repeated measures showed no group × time interactions. BRS = baroreflex sensitivity; Delta HR = difference between HR standing, HR during orthostatic stress, and supine HR; HF = high-frequency (wave); LF = low-frequency (wave); MBP = mean blood pressure; NA = not available; NU = normalized units; RMSSD = root mean square of successive differences; SBP = systolic blood pressure; St = standing; Sup = supine; W0 = week 0 (baseline).

† Group effect (ArTMS vs. SrTMS): *P* < 0.05 but no time interaction.

‡ Group effect (ArTMS vs. SrTMS): *P* < 0.01 but no time interaction.

§ Group effect (ArTMS vs. SrTMS): *P* < 0.001 but no time interaction.
the end of the intervention (Table 2). It is likely that this improvement in cardiorespiratory fitness was mainly due to the aerobic training, as previously shown (40), but a placebo effect of the intervention cannot be excluded.

Secondary FM outcomes (as measured by the FIQ, BDI, and PCS) improved (Table 2). Indeed, mean FIQ score decreased by ~11 points (17%) in both groups between baseline and W14 and was long lasting. Thus, the impact of FM on QoL in these patients diminished more than that reported previously (40) and was greater than the minimum clinically important difference (i.e., the intervention was efficient for this outcome and lasted at least 6 months) (32). A similar analysis was conducted for depression (using the BDI), which decreased (~27%) in both groups at W14, again by more than the minimum clinically important difference (41). This is in line with the literature, which describes mood improvements after programs involving aerobic exercises (8,40). Significant decreases in PCS scores were also seen at W14 in both groups, suggesting that FM patients increased their ability to cope with pain after the intervention. Decreased catastrophizing is an important issue because it is an indicator of poor outcomes of chronic pain, and in particular of severe physical disability (42).

In regard to the effects on HR and BP variability, no significant effect over time was shown in either group for any of the variables studied, including those not shown in Table 3 (mainly standing values). It is thus implied that neither rTMS nor MT altered cardiac autonomic system adaptations despite pain and fitness improvements. This suggests that different mechanisms are involved in regulatory pathways of pain and the cardiovascular autonomic system in FM, particularly after aerobic training (43,44). These results contrast with those of previous studies that showed that aerobic training had significant effects both on resting HR and HF power and sympathetic drive in healthy subjects and patients (see reviews in refs. 44 and 45). The effects of MT on the cardiac autonomic system in FM have been poorly investigated, although at-rest modifications are well described (43). To our knowledge, only 1 study has been published that showed improvements in HRV after aerobic training (34). In the current study, we cannot exclude the possibility that the exercise intensity or duration were not sufficient to provoke alterations in HRV. Nevertheless, patients underwent aerobic training sessions at higher intensity and more frequently than in the study of Sanudo et al (34).

There was a group effect at baseline that persisted throughout the study; the SrTMS group showing better vagal tone (lower resting HR, and higher RMSSD and HF components) (33). This could be related to the sex distribution between the groups (all men were allocated to the SrTMS group and had better cardiorespiratory fitness), which may influence HRV (46).

Tolerance and efficiency of rTMS and reconditioning were as follows: 34 of 39 randomized patients finished the 12-week intervention, corresponding to an attrition rate of 12.9%. This percentage was below the range in the literature (~20%) for programs

consisting of aerobic training (40,47). Tolerance was good, as only 1 patient dropped out after a flare of FM symptoms. The initiation phase of rTMS was well tolerated, as all the patients finished this session. Fifteen patients (38.4%) were good responders (PGIC score <3), with no significant difference between groups. This rate seems substantial in FM, although we found no data in the literature analyzing PGIC results after reconditioning.

In terms of study limitations and strengths, first, this trial was designed to demonstrate that rTMS plus MT is more effective than MT alone in reducing pain. Thus, a placebo effect of rTMS could not be excluded. We used a sham coil with size, color, and shape identical to the active coil. Both coils emitted the same sound, so patients could not distinguish between the sham and the active device.

Second, this study might be underpowered because we calculated a power of 32% and an effect size of 0.24 from the pain VAS of the sample. The original calculation of sample size was based on prior studies (19,25), with an hypothesis of 20% pain reduction with rTMS. This hypothesis was likely overestimated regarding the effect size of this study. Accordingly, 52 patients per group would have been needed to show a significant time x treatment interaction on a VAS for pain.

Third, one cannot exclude that another study design (e.g., one with a longer initiation phase, or one that started MT at a different time) might have been more efficient. Finally, only 10% of the patients who were screened were included in the study. It is possible that a selection bias occurred because some patients had difficulty joining the study due to its duration and time-related constraints. This also reflects the difficulty in combining MT and rTMS sessions over the same timeframe for patients experiencing pain and exhaustion.

In conclusion, this study showed that rTMS associated with MT did not induce greater reduction in pain than MT alone in patients with severe FM. The updated meta-analysis strengthens the results of this study, suggesting that rTMS is not effective in improving either pain or QoL in patients with severe FM.

## ACKNOWLEDGMENTS

We thank the physical therapists of the Institut de rééducation de rhumatologie (Grenoble Alpes University Hospital), in particular, Mrs. Anne Marie Sevenier, who permitted the continuity of this study. We thank Dr. Alison Foote (Grenoble Alpes University Hospital) for critically editing the manuscript.

## AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Guinot had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

**Study conception and design.** Guinot, Maindet, H. Hodaj, Bachasson, Cracowski, Launois.

**Acquisition of data.** Guinot, Maindet, Bachasson, Baillieul.

**Analysis and interpretation of data.** Guinot, Maindet, E. Hodaj, Cracowski.
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Erratum

DOI 10.1002/acr.24566

In the article by Fitzgerald et al in the June 2020 issue of *Arthritis Care & Research* (2020 American College of Rheumatology Guideline for the Management of Gout [pages 744–760]), under the section “High-fructose corn syrup” on page 754, the following sentence was incorrect: “In the National Health and Nutrition Examination Survey, artificially sweetened carbonated beverage consumption was associated with higher SU levels (101).” The correct sentence should be: “In the National Health and Nutrition Examination Survey, sugar-sweetened carbonated beverage consumption was associated with higher SU levels (101).”

We regret the error.