# Efficacy and mechanism of supervised adapted physical activity on quality of life for patients with fibromyalgia: single-center, prospective, randomised clinical and neuroimaging study

Stéphanie Ranque, Jérôme Laurin, Marius George Linguraru, Zhifan Jiang, Anderson Loundou, Laurent Boyer, Régis Guieu, José Boucraut, Caroline Sault, Jeremy Simon, et al.

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Stéphanie Ranque, Jérôme Laurin, Marius George Linguraru, Zhifan Jiang, Anderson Loundou, et al. Efficacy and mechanism of supervised adapted physical activity on quality of life for patients with fibromyalgia: single-center, prospective, randomised clinical and neuroimaging study. Scientific Reports, 2026, 16 (1), 10.1038/s41598-025-33433-5. http://dx.doi.org/10.1038/s41598-025-33433-5

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# Efficacy and mechanism of supervised adapted physical activity on quality of life for patients with fibromyalgia: single-center, prospective, randomised clinical and neuroimaging study

Stéphanie Ranque<sup>1,2,11✉</sup>, Jérôme Laurin<sup>3,11</sup>, Marius George Linguraru<sup>4,5</sup>, Zhifan Jiang<sup>4</sup>, Anderson Loundou<sup>6</sup>, Laurent Boyer<sup>6</sup>, Régis Guieu<sup>7</sup>, José Boucraut<sup>8</sup>, Caroline Sault<sup>1</sup>, Jeremy Simon<sup>1</sup>, Fanny Barthelemy<sup>2,9</sup>, Anne Donnet<sup>1,10,11</sup> & Eric Guedj<sup>2,9,11</sup>

Fibromyalgia (FM) is a chronic overlapping pain condition that impairs quality of life (QOL). Adapted physical activity (APA) is recommended as a key non-pharmacological intervention, though its implementation and underlying mechanisms remain limited. Fibromyalgia, a prospective, randomised, single-blind clinical and neuroimaging study, evaluated the efficacy and mechanisms of a structured, supervised APA program in FM. Seventy-nine adults were assigned to supervised APA (n = 39) or standard care (n = 40) and followed for 12 months. The intervention consisted of diversified, low-intensity, fractionated sessions three times weekly for 6 months. Outcomes included the Fibromyalgia Impact Questionnaire (FIQ, primary endpoint at M6), clinical and psychological scales, functional tests, pedometer monitoring, and mechanistic measures (<sup>18</sup>F-FDG PET, blood/urine biomarkers). Supervised APA produced significantly greater FIQ improvement and broader benefits across PGIC, Widespread Pain Index, Symptom Severity Scale, tender points, mean pain, sleep quality, flexibility, and daily step counts. Immediate symptom relief occurred after each session. Brain PET revealed increased metabolism in the right cerebellum in the APA group, correlating positively with step-count improvement. This interdisciplinary trial demonstrates that a reproducible supervised APA program yields sustained improvements in QOL, symptoms, and functional activity in FM, potentially mediated by cerebellar modulation of motor and behavioural engagement.

ClinicalTrials.gov identifier: NCT03640806 N°IDRCB:2017-A03011-52. Sponsor: Assistance Publique Hôpitaux De Marseille (Marseille Public Hospital System). Other Study ID Numbers: 2017-57.

**Keywords** Adapted physical activity, Fibromyalgia, Non-pharmacological intervention, Quality of life, Chronic pain, Widespread nociceptive pain, Neuroimaging, Brain PET 18F-FDG

<sup>1</sup>APHM, FHU INOVPAIN, Timone Hospital, Pain Assessment and Treatment Centre (CETD), Marseille, France.

<sup>2</sup>Aix Marseille Univ, CNRS, Centrale Med, Institut Fresnel, Marseille, France.

<sup>3</sup>Aix Marseille Univ, INSERM, INMED, Marseille, France.

<sup>4</sup>Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, D.C., USA.

<sup>5</sup>Departments of Radiology and Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, D.C., USA.

<sup>6</sup>Aix Marseille Univ, APHM, CEReSS, Plateforme d'aide méthodologique et biostatistique, Marseille, France.

<sup>7</sup>APHM, Timone Hospital, Service de Biochimie, Marseille, France.

<sup>8</sup>Aix Marseille Univ, INSERM, INS, Inst Neurosci Syst, Marseille, France.

<sup>9</sup>Nuclear Medicine Department, Aix Marseille Univ, APHM, Timone Hospital, CERIMED, Marseille, France.

<sup>10</sup>Université Clermont Auvergne, CHU Clermont-Ferrand, Neuro-Dol, INSERM, Clermont-Ferrand 63000, France.
Fibromyalgia (FM) is a chronic overlapping pain condition, defined by widespread nociplastic painful and nonpainful symptoms, impairing quality of life (QOL)¹⁻³. Often overlooked as a comorbid condition, FM affects approximately 3% of the population with variations depending on diagnostic criteria and methodology; women accounting for two-thirds of cases¹,²,⁴⁻⁶. In France, diagnostic and therapeutic wandering lasts roughly eight years before referral to a pain center⁷,⁸, leading to global functional decline, financial instability, and direct as indirect costs (€6,000 to €12,500/patient/year)⁹⁻¹².

No marketing authorization for pharmacological treatment exists in France¹³⁻¹⁵. Accordingly, international guidelines recommend nonpharmacological interventions (NPI) as first-line options, with adapted physical activity (APA) as a central component alongside health education, cognitive behavioral therapy, body-oriented psychotherapy¹,⁹,¹⁴,¹⁶. However, despite well-established hypoalgesic effects of exercise, patients with FM remain more sedentary and less physically active than the general population¹⁷⁻²⁰.

APA guidelines remain unclear due to methodological limitations of studies such as precise FITT criteria (frequency, intensity, type, duration of sessions), small sample size, short duration of APA and follow-up²¹,²²⁻²⁶. These issues hinder the ability to replicate and individualize APA programs, recommended to maintain benefits over time⁹,¹⁶,²⁵,²⁷,²⁸. Patients meet difficulties in implementing and adhering to APA even if properly informed and convinced, because of inadequate counseling, costs, lack of motivation for example¹⁶.

Additional methodological considerations are related to the relevant evaluation. In addition to clinical parameters, QOL factors such as symptom perception and global impression of change (PGIC) are relevant²,²⁹. Biological and neuroimaging measures have rarely included in prospective studies to ascertain underlying mechanisms³⁰,³¹. Finally, experimenters and outcome assessment blinding was poorly observed, despite being considered one of the primary risk-of-bias¹⁷.

In light of these considerations, Fibromyalactiv, a single-center, prospective, single-blind, randomised and controlled interventional study, aimed to evaluate the efficacy of a reproducible and interdisciplinary protocol of supervised APA program on the QOL and underlying mechanisms in patients with FM over one year. This interdisciplinary multi-professional approach used both classical and innovative assessments³². First, a battery of self-administered questionnaires or scales explored the functional, psychic, social, professional impact of FM and coping strategies. Then functional tests were performed such as clinical exams, the shuttle walking test (SWT), aerobic fitness appropriate for patients with FM)³³, bioimpedance analysis, pedometer. Finally, brain ¹⁸F-FDG PET was performed in a subgroup to explore cerebral mechanisms underlying APA effects³⁴. Fibromyalactiv was designed to provide symptomatic relief while promoting an active, autonomous lifestyle centered on individualized, structured, and pleasant APA. To our knowledge, no previous study has provided evidence combining both efficacy and mechanism of well-defined, supervised APA program. Such a reproducible interdisciplinary NPI program could help improve further studies & guidelines for patients¹,¹⁴,²⁶,³⁵.

## Methods

Fibromyalactiv is a single-center, prospective, single-blind, randomised, controlled interventional study.

### Regulatory aspect

Participants provided written informed consent before inclusion. The study received favorable opinions from the Patient Protection Committee (CPP) of Mediterranean South Marseille (2016), Kremlin Bicêtre Paris (2018) and from the Nuclear Safety Authority for Positron Emission Tomography Computed Tomography (PET-CT), registration with the IT and Freedom Committee of Marseille Public Hospital System (APHM) and compliance with general data protection regulation (RGPD). Authorization from the bioethics unit of the General Directorate for Research and Innovation has been obtained for the establishment of a biobank. The study was published on ClinicalTrials.gov: NCT03640806³⁴. Study ID N°IDRCB: 2017-A030-52. The full protocol is available at the « Direction de la Recherche Clinique et de l'Innovation », 80, rue Brochier 13,005 Marseille, France. Study Start: 2018-11-15; Primary completion 2020-06-30; Study completion 2020-08-10; Monitoring closure certificate 2025-05-27.

### Participants

Seventy-nine FM patients followed at the Pain Center (CETD), CHU Timone, Marseille, were randomised into two groups analyzed following usual phases of a two-group randomised trial: enrollment, allocation, follow-up, and data analysis (Fig. 1)³⁶:

* **Experimental group (A, n = 39):** Patients received standard of care⁹,¹³ plus supervised APA from D0 to M6.

* **Control group (B, n = 40):** Patients only received standard of care for 12 months.

The patients included were already followed at the CETD. They were consecutive patients who met the inclusion criteria defined by the protocol. The study was explained at the end of the consultation, and interested patients who met the inclusion criteria provided written consent. Sample size was calculated to detect a 10-point difference in FIQ (0–100) with an alpha risk of 5%, a power of 80%, and a sufficient margin for losses of view and study lefts. With a standard deviation of the measure of FIQ in the population estimated from the data of the medical literature.

Inclusion criteria involved patients with FM, meeting the American College of Rheumatology criteria³⁷, with an average pain > 4/10 at numeric scale, female or male, from 18 to 72 years old, with no contraindication to the practice of physical activity, and no contraindication to PET examination (pregnancy or breastfeeding). Their general state and comprehension of French made possible to complete a questionnaire. They read, understood and
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** CONSORT 2025 Flow Diagram³⁶. Fibromyactiv flowchart: progression through the phases of this randomised, two-group trial.</figcaption></figure>

signed informed consent. Patients had previously participated in therapeutic education workshops and carried out the Cognitive Behavioral Therapy assessment of management of rhythms, emotions and stress performed in the Pain Assessment and Treatment Centre (CETD), Timone Hospital, Marseille, France. Exclusion criteria involved subject under legal protection, deprived of liberty or unable to express their consent or presenting a contraindication to the practice of physical activity, as subject with psychiatric illness or personality disorder making group work difficult. Subjects withdrawing their consent were also excluded.

## Experimental protocol

The group A performed the supervised Fibromyactiv APA program from D0 to M6. The primary outcome was the changes in Fibromyalgia Impact Questionnaire (FIQ) at 6 months (M6) compared to day 0 (D0, baseline). Secondary outcomes included changes in the interdisciplinary assessment at 3 (M3), M6 and 12 months (M12) versus D0. From M6 to M12, a supervised APA without a predefined program was offered to all patients included. Duration of Fibromyactiv was 12 months per patient. Brain ¹⁸F-FDG PET imaging was conducted after completion of the first half of inclusions, at baseline and at 6 months in 17 patients from group A and 16 from group B.

Randomisation set up before the start of the study was centralized, 1:1, by computerized drawing of lots under CERESS methodologist blinded team. Blinding of experimenters and outcome assessment is poorly observed, despite being considered one of the primary risk-of-bias assessments¹⁷. Physical examinators, nurses,
psychologists, methodologists, and nuclear medicine teams assessing outcomes were blinded after assignment to interventions. The patients, APA supervisors and the principal investigator were not blinded but handled not revealing their group to the blinded people. All patients could practice autonomous physical activity any time and were evaluated at D0, M3, M6 and M12.

The data were collected in the CETD for scorings supervised by psychologist specialized in cognitive behavioral therapy, for physical and medical assessment by general practitioner specialized in pain and sport medicine, blood samples by CETD nurses and on computer for SWT by exercise physiologist. The PET-CT with ¹⁸F- FDG was performed at the European Center for Research in Medical Imaging (CERIMED), for the last 33 patients at inclusion (D0) and at 6 months (M6). For all the 79 participants, blood samples were analysed and stocked in APHM biobank and free urinary cortisol 24-hour cycle were collected by patients the day before and on the day of blood tests.

## APA program of fibromyalgia activity

This study aligned with the 2017 French Health Law³⁸ regarding the “prescription of physical activities” via FITT criteria, and the WHO Global Action Plan on Physical Activity 2018–2030²¹,³⁹,⁴⁰. Fifteen APA supervisors were trained in chronic pain management by expert patients⁴¹, psychologist, nurses, sport/pain practitioner to adapt their practice (Suppl Table 1).

## Supervised APA sessions

The patients in group A followed our supervised APA program for 6 months, consisting of sessions for 10 patients during 2 hours, 3 times per week (Monday, Wednesday and Friday from 10 a.m.) in Timone medical school gymnasium 13005, in Borély public parc 13008, in “Calanque” physiotherapists swimming pool 13008 or in “Orloff III” equestrian center 13012, Marseille, France. The warm-up and stretching exercises in the supervised sessions were taken from the “Bodily awakening” exercises of the booklet to create a common thread. Each session was supervised by a different APA supervisor following the same FITT Criteria²¹. Each week consisted of an aquagym session and two “dry” sessions, whose nature was unknown in advance by patients to keep motivation by arousing curiosity according to the same pattern (Suppl Table 2): (i) Assessment of symptoms before activity and warm-up (20 to 30 min); (ii) Low to moderate intensity supervised APA (60 min) was defined according to the maximum symptomatic time (MST) of each patient. MST is the time after which an exacerbation of symptom(s) occurs for a given activity, immediately or with a delay. The activity should have been performed during 50% of MST by splitting with recovery, (iii) Hydration, stretching, relaxation and assessment of symptoms after activity (30 min); (iv) A report, including an evaluation of symptoms (quality of sleep since the last session, pain, fatigue and mood) using scale of 0 to 10 of Likert type, 10 being the worst state and other feedback, and eventual harms, was carried out before and after each session. Moreover, the intensity of the perceived effort was recorded after the session (fatigue Borg's Rating of Perceived Exertion Scale; 6–20). Each feedback was transmitted by the APA supervisors to the P.I. to determine the content of each session; (v) After the first 6 months, all patients from A and B groups were offered a 6-month back-up program allowing them to continue or start supervised APA for free with supervisors trained by CETD, in their structures in town, to promote accessibility, to limit financial obstacles and the risk of poor supervision.

## Outcomes

### Primary outcome

The Fibromyalgia Impact Questionnaire (FIQ) is a self-administered score exploring 10 dimensions of FM impact on patients’ QOL. This fibromyalgia-specific QOL questionnaire assesses symptom intensity and the impact of FM on various life domains, including pain, fatigue, stiffness, mood, physical activity, social functioning, and household activities, among others. The weighted average of the responses to the 10 items yields a total FIQ score ranging from 0 to 100, with 100 representing the worst impact. We used its French adaptation and validation. We evaluate FIQ after 6 months (M6) of supervised APA (group A), compared with group B.

### Secondary outcome

A battery of self-administered questionnaires or scales explored the functional, psychic, social and professional impact of FM and the patient coping strategies. The quality of life was measured by the FIQ at other points than M6, i.e. M3 and M12. At each point, the overall quality of life was also assessed by the SF-36 score, the symptoms of the disease by the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS) diagnostic scores and the 18 tender points. The impact of chronic pain (QCD), the sleep rating using an 11-point Lickert-type numerical scale and the FSS Fatigue Scale completed the symptomatic evaluation. Anthropometric measurements were collected using bioimpedance analysis (Tanita BC-420MAP model) in addition to body mass index, hip size ratio. Moreover, asthenia, pain, mood, sleep and effort intensity were assessed at the end of each APA session in the A group using an 11-point Lickert-type numerical scale.

**Functional tests** Physical parameters included the measurements of strength (Arm Curl Test, Handgrip, Chair Stand), balance and coordination (Up and Go Test), flexibility (Chair Sit and Reach Test and Back Scratch, Straight Leg Raise test (SLR), Heel-Buttock Distance, Finger-Ground Distance) using the standard procedure for each test.

Physiological assessment was evaluated using the Shuttle Walking Test (SWT) to estimate aerobic fitness with simultaneous respiratory gas analysis. The SWT was conducted in a standardized 10-m corridor marked by two cones placed 0.5 m from each turning point. Participants walked or ran according to an externally paced audio signal. The initial speed was 0.5 m/s, increasing by 0.17 m/s every minute until volitional exhaustion or clinical interruption. Cardiorespiratory variables were collected continuously using a portable metabolic analyzer
(Cosmed K4b²). Before each test, the device was calibrated according to manufacturer recommendations and published CPET field protocols. Calibration included (i) ambient air calibration, (ii) gas mixture calibration (16% O₂, 5% CO₂), and (iii) turbine flow calibration using a 3-L syringe. Breath-by-breath VO₂, VCO₂, and ventilation were recorded throughout the test. For each stage, VO₂ values were averaged over the final 20 s to obtain representative steady-state values. Heart rate was recorded continuously. Ventilatory thresholds 1 and 2 (VT1, VT2) were determined using standard physiological criteria based on respiratory equivalents (VE/VO₂ and VE/VCO₂) and confirmed by two experienced evaluators. This methodology is consistent with previously published studies using the SWT and portable metabolic systems (including K4b²) in chronic pain and fibromyalgia populations.

Physical activity level was also collected by a short questionnaire Ricci and Gagnon on their physical activity habits and by wearing a pedometer for 8 consecutive days on D0, M3, M12 (OMRON model HJ-720ITCCAN). Psychic parameters were assessed by French Canadian Chronic Pain Self-Efficacy Scale (FC-CPSES), locus of control (IPC), anxiety and depressive symptoms (HADS scale), alexithymia (TAS-20). Patient motivation to change, which is of great importance in the possible definition of responder subgroups, was carried out using the PSOCQ questionnaire (Pain Stages of Change Questionnaire), coping strategies (CSQ), Kinesiophobia (TAMPA TSK), and stress (PSS-10). Improvement or decline in clinical status was assessed by the PGIC score.

## Assessment action mechanisms

### a) Brain ¹⁸F-FDG PET

Brain scans were acquired on GE Discovery PET/CT camera following international guidelines⁴²,⁴³. Imaging was performed with a three-dimensional protocol, 15-min scan 30 min after 150 MBq of ¹⁸F-FDG intravenous injection at rest. Image reconstruction incorporated attenuation correction based on the corresponding CT acquisition. Scans performed at baseline and M6 in 17 group A and 16 group B patients. Group X time Interaction was searched at whole-brain level using voxel-based SPM analysis (Wellcome Department of Cognitive Neurology, University College, London, UK). This analysis encompassed spatial normalization, 8 mm FWHM smoothing, global proportional scaling. The voxel threshold for significance was set at *p* < 0.001, with cluster size correction using Monte Carlo simulation (minimum 62 voxels). To control for potential confounding factors, we included age and sex as covariates. The identified metabolic cluster was extracted using MarsBaR (http://marsbar.sourceforge.net/), and Pearson's correlations were searched on exploratory analyses with clinical data (*p* < 0.001, to control for multiple tests).

### b) Blood sample and urine samples for cortisol immunoassay.

In addition to classic blood analyses (Blood count, Platelets, Sedimentation Rate, CRP), samples of blood were collected, centrifuged and frozen at -80 °C until analysis in Timone hospital, Marseille, France. Nf-L levels, pro-inflammatory cytokines (Il-1β, IL-6, IL-8, IL-17a, IFN-γ, TNF-α), anti-inflammatory cytokine (IL-10, IL-2), chemokines (IP-10, MCP-1, MIP-1 α, Eotaxin) and, vascular markers: VCAM-1, ICAM-1, VEGF), were quantified according to manufacturer's instructions.

In addition, a 24-hour urine sample was collected from each participant to quantify urine cortisol levels according to standard laboratory procedures.

## Statistical analysis

Statistical analysis was performed on the 79 randomised participants who reached at least M6, using IBM SPSS Statistics version 20 (IBM SPSS Inc., Chicago, IL, USA). Continuous variables are expressed as means +/- standard deviation or median with interquartile interval, and categorical variables are reported as count and percentages. Comparisons of means values between two groups were performed using student t-test or Mann-Whitney U. Comparisons of percentages were performed using Chi-Square test or (Fisher's exact test, as appropriate). The 95% confidence interval (CI) was calculated for FIQ, SF-36, PGIC, WPI, SSS, tender points, mean pain, sleep quality, fatigue, symptoms before and after APA, pedometer, physical parameters and psychic score measurements to provide an interval within which we can be 95% confident that the true population parameter lies. As subjects were followed overtime, repeated measures were made on the same statistical units, univariate and multivariate linear mixed-effects models were used. Variables significantly associated with outcomes and those deemed clinically meaningful in a univariate analysis were included into multivariate analysis. All the tests were two-sided. The statistical significance was defined as *p* < 0.05. The statistical analysis of neuroimaging data is described in detail in the dedicated section above.

## Results

### Recruitment and baseline

Inclusion allowed 1.5 months per group of 20, repeated 4 times, considering hypothetical refusals. Data management/statistics took 4 months, interrupted by SARS-CoV-2. No significant difference existed between groups A and B in Gender, Age, BMI, Smoking, 7-days pedometer count, professional activity, WPI, SSS, tender points or mean baseline pain at D0 (Suppl Table 3). All participants had moderate to severe FM based on the severity score from FIQ > 40 at D0.

### Primary endpoint (FIQ)

A greater improvement in FIQ was found at M6 compared to D0 (*p* = 0.03) in the group A compared to group B (-13.25 and + 1.2, respectively). Difference between groups was 14.5% (Table 1).
## Secondary endpoint

### FIQ

A significant improvement was found at M3 in group A for the FIQ score of -10.58 points (μB = +1.97, *p*=0.034). At M12, a tendency to improve the FIQ was still seen in group A with -9.65 points on average (μB = -0.13, *p*=0.167) (Table 1).

### Health-related quality of life (SF-36)

The analysis showed a significant difference in the sub-scores of physical abilities, social life and mental health at M12 compared to D0, with a greater improvement in group A than group B (*p*=0.02 for physical abilities, *p*=0.01 for social life, *p*=0.03 for mental health).

The mental composite score (MCS) was improved in group A to M12 (μA = +17.37%, μB = +3.1%, *p*=0.05). We also found a trend in group A for the improvement in physical capacities from M3 (*p*=0.07). The results were summarized in Table 2.

### PGIC

Means comparison found an improved PGIC in group A compared to group B at all evaluation times compared to D0 (M3: μE=2.60, μT=3.51, *p*=0.004; M6: μE=2.46, μT=3.43, *p*=0.004; M12: μE=2.69, μT=3.75, *p*=0.01) (Table 3). At all evaluation stages, the average group A PGIC was "better with no doubt a real improvement that makes the difference", while that of group B was "rather better but the change does not make a difference".

### Symptoms of the FM

**WPI, SSS and tender points (Table 4)** Between D0 and M3, there was a significant improvement in the Widespread Pain Index (WPI), the symptom severity score (SSS) and the number of tender points in group A compared to B.

**Average pain (QCD), quality of sleep (Likert type scale from 0 to 10), fatigue (FSS)** The mean pain was significantly reduced compared to D0 in group A compared to B from M3 with -7.11% on average for the item of the corresponding QCD (*p*=0.01). This result was also found at M6 (-7.43%, *p*=0.05) and up to M12 (-8.76%, *p*=0.02). The quality of sleep was also significantly improved at M6 in group A compared to B (+72.3%, *p*=0.04). No difference was found for the FSS (Table 5).

### Pedometer

At D0, patients from group A had nearly the same number of mean daily steps over 8 days (4185 ± 1883) than group B (4414 ± 1997). The analysis found a greater number of mean daily steps over 8 days in group A (5803 ± 2703) than group B (4455 ± 2048) at M3 (*p*=0.022). Between D0 and M3, group A gained 1619 ± 2244.5 daily steps on average, while group B lost 110 ± 1616.9 steps on average (*p*<0.0001). Between D0 and M12, a significant improvement in group A persisted compared to group B with +722 ± 1854.1 steps against -663 ± 1329.4 steps for group B (*p*=0.002) (Table 6a). In addition, we observed that maximal peak activity hour changed in group A: 3 h earlier at M3 (11:00 am) and 2 h earlier at M12 (noon) in comparison to D0 (2:00 pm). No change was found in B group (2:00 pm) (Table 6b).

### Physical parameters

**Aerobic fitness (SWT)** Any patient reached the ventilatory threshold 2 (VT2) and VO₂peak. Some subjects did not reach VT1 (23.7% at D0, including 36.8% of patients A and 63.1% of patients B, 19.7% at M3 including 50% B and 50% A, 16.1% at M12 including 20% B and 80% A) meaning that the test had been stopped mainly because of pain or shortness of breath (Supplementary Table 4).

**Physical assessment** In terms of strength, the left Arm Curl Test strongly tended to be improved in group A compared to B between D0 and M3 (*p*=0.07) (Supplementary Table 5).

In terms of flexibility, we found a significant improvement in the SLR test in group A between D0-M3 on both sides (*p*=0.03 on the right and *p*=0.04 on the left). The right Back Scratch was improved in group B between D0-M3 while it declined in group A (*p*=0.03). This difference was no longer observed at M12 where it declined for the two groups.

<table><caption>**Table 1.** FIQ between D0 and other time points. FIQ: Score from 0 to 100, 100 being the worst possible state; *p-value from Student's test; CI: Confidence Interval. Δ Primary endpoint μ=mean; SD=Standard Deviation of mean difference.</caption><thead><tr><th></th><th></th><th>μ</th><th>SD</th><th>p-value*</th><th>μ difference</th><th>CI95% of difference</th></tr></thead><tbody><tr><td rowspan="2">D0-M3</td><td>A</td><td>-10.58</td><td>23.10</td><td rowspan="2">0.034</td><td rowspan="2">12.52</td><td rowspan="2">[0.98; 24.12]</td></tr><tr><td>B</td><td>1.97</td><td>27.70</td></tr><tr><td rowspan="2">D0-M6<sup>Δ</sup></td><td>A</td><td>-13.25</td><td>2.38</td><td rowspan="2">0.030</td><td rowspan="2">14.45</td><td rowspan="2">[1.39; 27.50]</td></tr><tr><td>B</td><td>1.20</td><td>31.84</td></tr><tr><td rowspan="2">D0-M12</td><td>A</td><td>-9.65</td><td>25.26</td><td rowspan="2">0.167</td><td rowspan="2">9.52</td><td rowspan="2">[-4.07; 23.11]</td></tr><tr><td>B</td><td>-0.13</td><td>31.19</td></tr></tbody></table>
<table><caption>**Table 6.** Pedometer analysis. *p-value from Student test; μ = mean daily steps; SD = Standard Deviation; CI: Confidence Interval. SD = Standard Deviation.</caption><thead><tr><th colspan="6">a: Daily activity</th></tr><tr><th></th><th></th><th>μ</th><th>SD</th><th>p-value*</th><th>CI 95% of the difference</th></tr></thead><tbody><tr><td rowspan="2">D0</td><td>A</td><td>4185</td><td>1883</td><td rowspan="2">0.606</td><td rowspan="2">[-1110.6; 652.5]</td></tr><tr><td>B</td><td>4414</td><td>1997</td></tr><tr><td rowspan="2">M3</td><td>A</td><td>5803</td><td>2703</td><td rowspan="2">0.022</td><td rowspan="2">[199.1; 2497.7]</td></tr><tr><td>B</td><td>4455</td><td>2048</td></tr><tr><td rowspan="2">M12</td><td>A</td><td>4901</td><td>2221</td><td rowspan="2">0.166</td><td rowspan="2">[-323.8; 1845.3]</td></tr><tr><td>B</td><td>4140</td><td>2069</td></tr><tr><td rowspan="2">D0-M3</td><td>A</td><td>1619</td><td>2244.5</td><td rowspan="2">&lt;0.0001</td><td rowspan="2">[789.5; 2667.8]</td></tr><tr><td>B</td><td>-110</td><td>1616.9</td></tr><tr><td rowspan="2">D0-M12</td><td>A</td><td>722</td><td>1854.1</td><td rowspan="2">0.002</td><td rowspan="2">[544.2; 225.5]</td></tr><tr><td>B</td><td>-663</td><td>1329.4</td></tr></tbody></table><table><thead><tr><th colspan="8">b: Maximal activity peak hour</th></tr><tr><th>Group</th><th>Peak Steps D0</th><th>Peak Hour D0</th><th>Peak Steps M3</th><th>Peak Hour M3</th><th>Peak Steps M12</th><th>Peak Hour M12</th></tr></thead><tbody><tr><td>A</td><td>700</td><td>14</td><td>862</td><td>11</td><td>786</td><td>12</td></tr><tr><td>SD</td><td>294</td><td>3</td><td>389</td><td>3</td><td>362</td><td>3</td></tr><tr><td>B</td><td>738</td><td>14</td><td>690</td><td>13</td><td>766</td><td>14</td></tr><tr><td>SD</td><td>397</td><td>3</td><td>328</td><td>4</td><td>418</td><td>3</td></tr></tbody></table>

## Blood and urine samples

No significant results were found for both blood and urine markers (data not shown).

## Discussion

### Supervised adapted physical activity induces durable symptom-related, behavioral, and neurofunctional improvements in fibromyalgia when it is individualized, non-painful, and embedded in a supportive framework

Participants receiving supervised APA exhibited broader and earlier benefits than those receiving standard care alone, with improvements spanning global functional impact, perceived change, pain experiences, sleep quality, flexibility, and daily activity. These multidimensional gains, maintained up to 12 months, suggest that the Fibromyactiv program may act on the interplay between physical symptoms, emotional responses, and behavioural patterns that sustain FM burden. Importantly, these improvements occurred despite the absence of measurable gains in maximal aerobic capacity. This reinforces that, in FM, effective activity programs do not rely on high-intensity training or cardiovascular conditioning but rather on individualized, enjoyable, non-painful, supportive approaches. The systematic use of pre- and post-session symptom assessments likely contributed to adherence by encouraging immediate positive feedback and helping patients identify effort levels that remain safe and acceptable.

The improvement in global functional status reinforces the potential of APA to induce long-term benefits in quality of life³⁴,⁴⁴. At 12 months, maintaining these gains may reflect patient empowerment and increased autonomy. These findings were in line with changes observed across physical, social, and psychological domains, consistent with SF-36 results and current recommendations⁹,¹⁴,¹⁵,²⁸. The sustained improvement in patients' overall perception of change further reflects a meaningful subjective sense of recovery, often linked to enhanced self-efficacy¹⁰. This perceptual dimension appears particularly valuable for evaluating APA in FM, as it captures the experiential aspects of improvement not fully reflected in other scores²,²⁹,⁴⁵,⁴⁶. In the trained group, the stable reduction in pain and symptom burden suggests a partial but lasting attenuation of perceived disease activity, supported by improved sleep and decreased daily discomfort during the supervised phase.

Behavioural adaptations also played a central role. Increased daily physical activity and earlier timing of peak activity are consistent with studies linking symptom severity to delayed activity rhythms⁴⁷. These findings suggest that APA may contribute to a more functional circadian organization of activity⁴⁸. Supervision seems essential for enabling patients to modify daily habits, overcome avoidance behaviours, and progressively adopt a more active lifestyle⁴⁷. Pedometer monitoring, used throughout the intervention, likely supported motivation through a neurofeedback effect and may serve as a prognostic marker for multimodal therapy. This aligns with evidence showing that reaching at least 4 500 steps/day is associated with reduced all-cause mortality⁴⁹ and might represent a realistic behavioural target for FM.

From a physiological standpoint, our findings confirm the difficulty for patients with FM to reach VO₂peak⁵⁰⁻⁵², VT2, or predicted maximal heart rate due to pain, fatigue, or anticipatory anxiety. The dissociation between aerobic capacities and clinical improvement aligns with previous reports indicating that increased fitness is not required for QOL enhancement⁵⁰,⁵²,⁵³. In our study, the supervised group showed symptomatic improvement without aerobic gains, while the control group increased fitness but showed reduced QOL at M3, sometimes leading to dropout. This supports the idea that unsupervised or performance-oriented exercise may be counterproductive in FM. Consequently, varied, regular, effortless, non-algogenic practice appears more
<figure><img src="image_4.png" /><figcaption>**Fig. 2.** 18 F-FDG PET findings in patients with fibromyalgia. (a) Increased metabolism of the right cerebellum found in group A compared to group B over the 6-month follow-up period (p-voxel <0.001, peak T-score = 3.81, k = 79). (b) This improvement of cerebellum metabolism was positively correlated with the improvement of pedometer performance at 3 months (r = 0.613; *p* = 0.00019).</figcaption></figure>

realistic and acceptable for individuals living with chronic pain and exhaustion—challenging the traditional “no pain, no gain” paradigm. The SWT nonetheless remains a useful tool to guide individualized APA intensity.

Neuroimaging analysis showed that clinical and behavioural improvements were associated with enhanced metabolism in the cerebellar motor region, correlating with increased daily activity. This observation is coherent with previous findings describing cerebellar dysfunction in FM, including hypoperfusion⁵⁴ altered gray matter⁵⁵⁻⁵⁷, and disrupted connectivity with limbic and prefrontal regions⁴³,⁵⁸. It also echoes PET studies showing cerebellar hypometabolism during physical inactivity⁵⁹. Since the cerebellum contributes not only to motor control but also to pain modulation, emotional regulation, and cognitive processes⁵⁵,⁵⁷,⁶⁰, its involvement suggests that APA may promote activity-dependent neuroplasticity in pathways relevant to FM. The association between cerebellar metabolism and activity change supports the hypothesis that the cerebellum may serve as a sensitive biomarker of APA responsiveness.

The Fibromyactiv program integrated several methodological strengths, including individualization, program duration, adherence to FITT criteria²¹, and diversity of APA modalities supervised by a multidisciplinary team³². The inclusion of strategies aimed at counteracting avoidance behaviours (e.g., kinesiophobia), maintaining engagement through varied and non-repetitive sessions, and systematically evaluating symptoms before and after APA—with consistently positive feedback—likely enhanced motivation and tolerance. Long-term follow-up and a lower withdrawal rate than typically reported in Cochrane reviews²²⁻²⁵,⁶¹ further highlight the feasibility and
acceptability of the program. Offering low-cost activity options after the supervised phase also helped mitigate financial barriers and limited access to APA resources.

Overall, this study supports patient-centered approaches for chronically painful and sedentary populations, emphasizing the importance of tailored and varied APA rather than uniform general advice. Independent practice or participation in standard sports clubs often fails due to insufficient adaptation to individual limitations and symptom fluctuations. A guide for caregivers, APA supervisors, and patients could help standardize recommended practices. Early APA integration within multimodal care may reduce healthcare utilization and limit pharmacological escalation²⁶. Tools such as individualized symptom scales, Borg ratings, and reproducible APA material³⁵ could support the development of structured guidelines for APA as an NPI in FM.

## Methodological limitations

Several limitations should be considered. Participants were recruited from a specialized pain center and had prior therapeutic education, which may limit generalizability and increase baseline motivation. As in any NPI, spontaneous activity in the control group could not be controlled, and pedometer use may have influenced behaviours. Participation decreased during summer months, highlighting environmental impact on adherence. Despite standardization, supervisor and activity diversity may introduce variability, but compliance with the “FITT” criteria, the jointly constructed common booklet and the systematic transmission before and after the APA session to a single coordinator throughout the research led to a homogeneous and reproducible program²¹,³⁵. The neuroimaging subgroup was relatively small; mechanistic conclusions should therefore be interpreted cautiously and confirmed in larger cohorts.

## Conclusion

Fibromyaactiv, a structured and reproducible supervised APA program, leads to sustained improvements in QOL, various symptoms, and functional activity in FM, outperforming unsupervised general advice. Its design—low-intensity, varied, pain-free and adapted exercises, and centered on patient enjoyment—appears crucial for long-term engagement.

Mechanistically, clinical benefits were associated with increased cerebellar metabolism and enhanced daily activity, supporting a link between APA participation, motor network modulation, and behavioural change. These findings reinforce APA as a practical and scalable non-pharmaceutical intervention in FM and highlight the importance of individualized, pleasant, and diversified activities rather than performance-driven exercise¹⁷,²⁶. Future studies should clarify cerebellar contributions to APA responsiveness and refine guidelines to promote sustainable, patient-centered therapeutic programs in chronic pain populations.

## Data availability

All data are available upon reasonable request to the corresponding author. The investigators will share data (with associated coding library) used in developing the results presented in this manuscript on request to the corresponding author at stephanie.ranque@ap-hm.fr. Anonymized record level data will be made available on proposal for analysis by those who have received ethical clearance from their host institution.

Received: 17 November 2025; Accepted: 18 December 2025

Published online: 03 February 2026

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## Acknowledgements

We thank the data safety monitoring board members: Anderson Loundou for their insightful suggestions concerning the study protocol; Nathalie Agnes Carole Talbi, the nurses, and Jeremy Simon psychologist of Pain Evaluation and Treatment Center for their help with various aspects of the study; A special thank you to all the medical students who participated in this research and presented their doctoral thesis in medicine on the subject at the Medicine School Timone, Marseille, France, Dr A Zerdab (2016) Dr D. Lafargue (2017), Dr AS Rouvière (2017), Dr L Bertin Maghit Bellon, Dr M Pocris (2020), Dr M Claude (2020), Dr A Jacob (2022). We'd like to thank also Expert patients and Mestre Juruna, Yannique Bourglan, Céline Maye, Alexis Dumelie, Magali Romagnan, Florence Morel, Mikael Richaud, Morgane Lozachmeur, Matthieu Gonnet, Eliecy Santos, Typhanie Montes, Clothilde Aira, Manon Nallis, Mélissa Depierre, Emilien Lepine, Marco Becherini, Lionel Lefèbvre, Guillemette Pouliquen for their expertise in APA supervisation; Annabelle Excoffon Isabelle Petit, Rakyia Quier Maraoui, Gilles Gravier, Dominique Tian, Alain Ferrero, Dr Champsaur, and the study participants, whose cooperation, encouragement, and enthusiasm were an inspiration to the investigators.

## Author contributions

SR, JL, EG, and AD act as guarantors of this study. SR, LB, AL, JS designed the study. SR obtained funding. SR, JL, JS, CS, RG, JB, FB and EG acquired the data. AL and LB carried out the statistical analysis. SR, JL, MGL, ZJ, AL, LB, RG, JB, CS, JS, AD and EG analyzed, interpreted the data, wrote the manuscript. All authors had full access to all anonymous data (including statistical reports and tables) in the study and can take responsibility for the integrity and accuracy of the data analysis. All authors have revised, read and approved the final version of the manuscript and agree with the order of authors.

## Funding

This study was supported by the “Prix Jeune Chercheur Casden/Fondation de l’Avenir 2016” grant. The contents of this manuscript are solely the responsibility of the authors and do not represent the official views of “Casden/Fondation de l’Avenir”. The organizations had no role in the study designed, conduct, data management, analysis, interpretation or manuscript preparation nor decision to submit the manuscript for publication. Agreements have been signed with the Dean of the Medicine School of Marseille for a gymnasium, with physiotherapists for the swimming pool of their center and with an equestrian center. Funding for APA supervisors came from main structures (town hall, regional and departmental council, sport ministry). Partnership contracts were created for downstream proposals with other sports associations.

## Declarations

### Competing interests

The authors declare no competing interests.

### Additional information

**Supplementary Information** The online version contains supplementary material available at https://doi.org/10.1038/s41598-025-33433-5.

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