Functional Brain MRI to Understand Pain Phenotypes in Knee Osteoarthritis (INDIGO)

Functional Brain MRI to Understand Pain Phenotypes in Knee Osteoarthritis: a Multicenter Comparative Pilot Study

Some people with knee osteoarthritis (gonarthrosis) experience pain differently. In some, the pain is described as "nociceptive" (directly related to the joint), while in others it has "neuropathic" characteristics (related to nerve function).

The goal of this multicenter, cross-sectional and comparative study is to compare resting brain activity in a brain region called the anterior insula among female patients with painful knee osteoarthritis who experience nociceptive pain compared to those with neuropathic pain.

Researchers will compare brain activity at rest between these two types of pain in women over 40 with painful knee osteoarthritis. A better understanding could help improve pain management in the future.

Participants will be asked to :

• complete questionnaires during the inclusion visit and on the day of the scan,
• undergo a clinical examination and a blood test at the inclusion visit,
• undergo a functional MRI (fMRI), an imaging test that allows observation of brain activity at rest.

Paticipants in the study does not involve any additional treatment. the fMRI scan is non-invasive and does not require any injections.

Study Overview

• Status: Not yet recruiting
• Conditions: Gonarthrosis; Neuropathic Pain, Nociceptive Pain
• Intervention / Treatment: Biological: blood sampling; Procedure: Resting-state functional MRI

Detailed Description

This study will include patients with painful knee osteoarthritis (pain scoring ≥ 4/10 on the Numerical Rating Scale (NRS)). Patients matched by age (within 3 years) will be divided into two groups based on their PainDETECT score: those with nociceptive pain (score ≤ 12) and those with neuropathic pain (score > 13).

Participants will be recruited from three rheumatology centers (30 in Clermont-Ferrand, 15 at Saint-Antoine Hospital, and 15 at Pitié-Salpêtrière Hospital in Paris). The rheumatologist will verify eligibility and provide information during the pre-enrollment consultation, within 30 days prior to enrollment. After obtaining their informed consent, patients will attend the enrollment visit and be assigned to a group based on their PainDETECT score.

Each participant will undergo a clinical evaluation, including the following PRO measures: Lequesne and WOMAC functional indices, EuroQol EQ-5D, Hospital Anxiety and Depression Scale, fatigue and pain intensity scales, Catastrophizing Scale (PCS), ICOAP, OASIS, and Flare-OA scales. A QST test will also be performed using the Neogi method, which includes pressure pain thresholds, conditioned pain modulation, and temporal pain summation.

A blood test will be performed, including high-sensitivity CRP and metabolic markers (lipid profile, HbA1c, and fasting blood glucose), due to the link between metabolic syndrome and osteoarthritic pain.

Within 30 days of enrollment, participants will undergo an fMRI scan at the radiology department in Clermont-Ferrand or at La Pitié-Salpêtrière. On the day of the scan, participants will complete additional self-reports of knee pain using the questionnaires. Interpretation of the fMRI data will be centralized in Clermont-Ferrand.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lise Laclautre; Phone Number: 0473754963; Email: promo_interne_drci@chu-clermontferrand.fr

Study Locations

• France
  • Clermont-Ferrand, France
    • CHU Clermont-Ferrand
    • Principal Investigator: Sylvain MATHIEU
    • Contact: Lise Laclautre; Phone Number: 0473754963; Email: promo_interne_drci@chu-clermontferrand.fr
  • Paris, France
    • APHP - Pitié-Salpêtrière
    • Contact: Florian BAILLY; Phone Number: +33142161194; Email: Florian.bailly@aphp.fr
    • Principal Investigator: Florian BAILLY
  • Paris, France
    • APHP - Saint-Antoine
    • Principal Investigator: Jérémie SELLAM
    • Contact: Jérémie SELLAM; Phone Number: +33149282520; Email: Jeremie.sellam@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Women aged 40 or older (only women will be included to ensure consistency in the analyses, given the higher prevalence of osteoarthritis in women and the influence of sex/gender on the experience of pain)
• Diagnosis of femorotibial osteoarthritis of the knee according to the 1986 American College of Rheumatology criteria
• Presence of knee pain with an intensity of ≥ 4/10 on a numerical rating scale (NRS)
• Chronic knee pain, i.e., lasting at least 6 months with at least 15 days of pain in the past 30 days
• Completion of the PainDETECT questionnaire, which will allow the patient to be assigned to one of two groups prior to the enrollment visit (those with nociceptive pain [score ≤ 12] and those with neuropathic pain [score > 13])
• Patients have read and understood the information letter
• Patients have signed the informed consent form
• Patients are enrolled in a social security program

Exclusion Criteria:

• Other joint diseases affecting the knees (gout, chondrocalcinosis, rheumatoid arthritis, spondyloarthritis, psoriatic arthritis)
• Conditions that, in the investigator's opinion, interfere with the assessment of osteoarthritic pain, such as conditions causing neuropathic pain in the lower extremities (e.g., peripheral neuropathy, chronic radiculopathy) or fibromyalgia
• Kellgren-Lawrence radiographic stage IV in one or both knees
• Patients with one or more knee prostheses
• Claustrophobia making MRI impossible
• Contraindication to MRI
• Pregnant or breastfeeding women
• Patients under guardianship, conservatorship, deprived of liberty, or under judicial protection
• Patients who have participated in an interventional clinical trial within the last 6 months that could impact the primary endpoint

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Nociceptive pain knee osteroarthritis; Participants with painful knee osteoarthritis classified as having nociceptive pain based on PainDETECT questionnaire score ≤12.	Biological: blood sampling; Blood sampling will be performed at the inclusion visit. A biological assessment will include high sensitivity C reactive protein (hs-CRP) and metabolic markers (lipid profile, HbA1c, and fasting glucose). Additional blood samples (4 tubes) will be collected for biobank, including plasma and serum storage for the measurement of inflammatory markers.; Procedure: Resting-state functional MRI; Resting-state functional brain MRI will be performed at Visit 2 (within 30 days of the screening visit). Participants will undergo a brain MRI acquisition at rest to evaluate anterior insula activity and functional connectivity with pain-related brain regions.
Other: Neuropathic-like pain knee osteoarthritis; Participants with painful knee osteoarthritis classified as having neuropathic-like pain based on PainDETECT questionnaire score >13.	Biological: blood sampling; Blood sampling will be performed at the inclusion visit. A biological assessment will include high sensitivity C reactive protein (hs-CRP) and metabolic markers (lipid profile, HbA1c, and fasting glucose). Additional blood samples (4 tubes) will be collected for biobank, including plasma and serum storage for the measurement of inflammatory markers.; Procedure: Resting-state functional MRI; Resting-state functional brain MRI will be performed at Visit 2 (within 30 days of the screening visit). Participants will undergo a brain MRI acquisition at rest to evaluate anterior insula activity and functional connectivity with pain-related brain regions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting-state anterior insula activity measured by functional MRI (BOLD signal amplitude)	Comparison of resting-state anterior insula brain activity between patients with painful knee osteoarthritis with nociceptive pain and those with neuropathic-like pain, classified using the painDETECT questionnaire.	At Visit 2 : within 30 days after inclusion, following Visit 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional connectivity of the anterior insula with pain-related brain regions (resting-state MRI)	Functional connectivity between the anterior insula (seed region) and predefined pain-related brain regions (S1, M1, posterior incula, ACC, MCC, vmPFC, DLPFC, thalamus) will be quantified using seed-basing resting-state fMRI analysis. Connectivity values will be expressed as Fisher-transformed correlation coefficients (z-scores).	At Visit 2 : within 30 days after inclusion
Correlation between clinical pain scores ans anterior insula activity (resting-state fMRI)	Correlation between clinical pain measures collected at visit 1 (painDETECT score, BAS pain intensity, WOMAC pain subscale, ICOAP score) and anterior insula activity measured at visit 2. Anterior insula activity will be quantified using the beta coefficient from the general linear model (GLM) of resting-state fMRI.	Clinical measures at Visit 1 and imaging measures at Visit 2 (within 30 days after inclusion)
Correlation between clinical pain scores ans anterior insula functional connectivity (resting-state fMRI)	Correlation between clinical pain measures collected at visit 1 (painDETECT, VAS, WOMAC, ICOAP) and functional connectivity z-scores between the anterior insula ans pain-related brain regions measured at visit 2.	Clinical measures at visit 1 ; imaging at visit 2 (within 30 days after inclusion)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient clusters identified using multimodal analysis including functional MRI and clinical data	Identification of patient subgroups based on multimodal integration of imaging and clinical variables	Data collected at Visit 1 and Visit 2 (within 30 days after inclusion)

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand
• Investigators: Principal Investigator: Sylvain MATHIEU, University Hospital, Clermont-Ferrand

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028

Study Registration Dates

• First Submitted: April 24, 2026
• First Submitted That Met QC Criteria: June 23, 2026
• First Posted (Actual): June 25, 2026

Study Record Updates

• Last Update Posted (Actual): June 25, 2026
• Last Update Submitted That Met QC Criteria: June 23, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Neuropathic pain; Gonarthrosis; Functional MRI; Nociceptive Pain; Anterior insula; Brain activity in the anterior insula at rest; INDIGO
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Neuromuscular Diseases; Arthritis; Joint Diseases; Rheumatic Diseases; Peripheral Nervous System Diseases; Osteoarthritis; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Osteoarthritis, Knee; Neuralgia; Nociceptive Pain; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: AOI 2025 MATHIEU; 2025-A02366-43 (Other Identifier: ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No