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The goal of this mechanistic clinical trial is to learn how physical exercise affects the body and brain in people with chronic low back pain. The study will examine whether a 12-week online exercise program changes these measures compared with a waitlist group. Researchers will also study immune activity and brain function in people with chronic low back pain and compare them with healthy participants. Participants will complete questionnaires, provide blood samples, and undergo brain imaging scans.
Chronic low back pain (CLBP) is the leading cause of disability worldwide, yet its underlying mechanisms remain poorly understood, limiting treatment effectiveness. Growing evidence suggests that CLBP is not solely driven by peripheral tissue pathology but involves maladaptive interactions between the immune system and the brain, particularly within reward- and emotion-related brain circuits. Physical exercise (PE) is universally recommended for CLBP and is known to influence both inflammatory processes and brain function, but the neuroimmune mechanisms through which PE alleviates pain are largely unknown. This study aims to address this critical gap by characterizing immune, neural, and autonomic alterations in CLBP and their modulation through structured PE training.
In this mechanistic randomized controlled trial, 144 individuals with CLBP will be randomized to a 12-week online PE program or a waitlist control, and 72 age- and sex-matched healthy controls will serve as comparators for baseline values and response to acute PE. Participants will undergo comprehensive assessments including questionnaires, movement-evoked pain testing, quantitative sensory testing, heart rate variability, blood sampling for immune gene expression (through whole blood transcriptomics), and multimodal MRI. Acute immune and autonomic responses to initial exercise sessions will also be examined to test whether short-term pro-inflammatory responses initiate longer-term adaptive and analgesic processes. By integrating immune, brain, and behavioral data, this study seeks to elucidate how neuroimmune interactions contribute to CLBP persistence and recovery, providing mechanistic insights to optimize exercise-based treatments.
In June 2025, the investigators initiated an initial pilot phase within the present trial to determine the feasibility of our recruitment strategies (recruitment of patient cohorts of 5-8 patients who will receive the PE intervention or be waitlisted according to block randomization) and compliance with the exercise program/waitlist protocol, and all intermediary data collection points. Feasibility was confirmed in February 2026, and recruitment of subsequent cohorts is planned to continue in March 2026. All future data collection will use the same core procedures and outcomes as the pilot phase, therefore, data collected during the pilot phase will be retained and may be included in the final analyses where appropriate.
At the time of this registration, preliminary analyses have only been conducted for the primary clinical outcome (pain intensity) as part of our assessment of feasibility. No inferential analyses have been conducted. Analyses of biological and neuroimaging measures, including transcriptomic and brain imaging data, are contingent on funding acquisition.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active intervention | Experimental | Physical Exercise Training |
|
| Waitlist | No Intervention | Participants assigned to the waitlist group will not receive the physical exercise program during the 12-week intervention period but will continue their usual care. After completion of the study assessments, they will be offered access to the exercise program. | |
| Healthy controls | Other | Sex- and age-matched healthy volunteers will only participate in the first 2 weeks of PE intervention |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Physical Exercise | Behavioral | Patients in the PE training group will perform a 12-week online program comprising three 60-minute weekly training sessions. The training program is delivered by certified kinesiologists through a secured online platform. Healthy controls will participate only in the first 2 weeks of PE training. |
| Measure | Description | Time Frame |
|---|---|---|
| Chronic Low Back Pain Intensity | Self-reported low back pain intensity averaged over the past 7 days, measured using an 11-point Numerical Rating Scale (NRS; 0-10), where 0 = "no pain" and 10 = "worst imaginable pain." Item from the NIH minimum dataset on research standards for chronic low back pain. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12). In addition, assessed daily through electronic pain diaries. |
| Measure | Description | Time Frame |
|---|---|---|
| Peripheral Blood Gene Expression (RNA Sequencing) | Gene expression levels assessed in peripheral blood using RNA sequencing. Transcriptomic analyses evaluated differential gene expression and pathway analyses. | Blood samples collected at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12). In addition, samples also collected 14, 48 hours and 2 weeks after the first exercise session or at equivalent times for waitlist participants |
| Measure | Description | Time Frame |
|---|---|---|
| Pain Catastrophizing Scale | The Pain Catastrophizing Scale (PCS) assesses catastrophic thinking related to pain, including rumination, magnification, and helplessness. The scale contains 13 items rated on a 5-point scale (0-4). Total scores range from 0 to 52, with higher scores indicating greater pain catastrophizing. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
Inclusion Criteria-CLBP patients:
Inclusion Criteria-Healthy controls:
- Be over 18 years and under 75 years of age;
Exclusion Criteria-CLBP patients:
Exclusion criteria-Healthy controls:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Carlos Gevers Montoro, PhD | Contact | +1-8199790448 | carlos.geversmontoro@mcgill.ca |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Montreal General Hospital | Recruiting | Montreal | Quebec | H3H 1V6 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38755449 | Background | Kaplan CM, Kelleher E, Irani A, Schrepf A, Clauw DJ, Harte SE. Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms. Nat Rev Neurol. 2024 Jun;20(6):347-363. doi: 10.1038/s41582-024-00966-8. Epub 2024 May 16. | |
| 38670108 | Background | Langston PK, Mathis D. Immunological regulation of skeletal muscle adaptation to exercise. Cell Metab. 2024 Jun 4;36(6):1175-1183. doi: 10.1016/j.cmet.2024.04.001. Epub 2024 Apr 25. |
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The study is currently still in a feasibility stage, this will be determined later
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 20, 2026 | Mar 16, 2026 | SAP_000.pdf |
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| ID | Term |
|---|---|
| D007249 | Inflammation |
| D059350 | Chronic Pain |
| D009043 | Motor Activity |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
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| ID | Term |
|---|---|
| D015444 | Exercise |
| ID | Term |
|---|---|
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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Mechanistic clinical trial in which two patient groups are randomized to two parallel arms (physical exercise vs waitlist), and a group of healthy controls are recruited to compare biological variables.
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Outcome assessors and data analysts will be blinded to group allocation
|
| Nucleus Accumbens-Medial Prefrontal Cortex Functional Connectivity | Functional connectivity assessed using resting-state functional magnetic resonance imaging (rsfMRI). Seed-to-voxel analyses performed using anatomically defined bilateral nucleus accumbens and medial prefrontal cortex regions. | MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Fractional Anisotropy of NAc-mPFC White Matter Tract | Fractional Anisotropy (FA) measured using diffusion-weighted imaging (DWI) probabilistic tractography along the white matter connecting the nucleus accumbens and medial prefrontal cortex. | MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Whole-Brain Intrinsic Connectivity | Intrinsic connectivity analysis (voxel-wise network centrality; root mean square of all functional connections) performed using resting-state functional magnetic resonance imaging (rsfMRI) to quantify whole-brain functional connectivity. | MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Tonic Pain Signature (ToPS) | Expression of the Tonic Pain Signature (ToPS), a multivariate brain biomarker derived from whole-brain functional connectivity patterns predictive of sustained pain intensity. The ToPS score will be computed from resting-state fMRI data using validated model weights and applied to participant-level connectivity matrices. | MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Nociplastic Functional Signature (NFS) | Expression of the Nociplastic Functional Signature (NFS), a brain-based connectivity biomarker trained to classify nociplastic pain conditions. NFS scores will be calculated from resting-state fMRI connectivity patterns to quantify the presence of nociplastic pain-related network dysconnectivity. | MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Hippocampal volume | Structural volume of the bilateral hippocampus measured from T1-weighted anatomical MRI using automated segmentation. Hippocampal volume alterations have been reported in chronic pain populations and may reflect changes associated with pain chronification. | MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Superior Longitudinal Fasciculus (SLF) White Matter Integrity | Microstructural integrity of the Superior Longitudinal Fasciculus (SLF) assessed using DWI metrics (fractional anisotropy, mean diffusivity). The SLF is a major fronto-parietal white-matter tract implicated in cognitive control, attention, and pain modulation networks. Loss of integrity in this tract may be associated with chronic pain severity. | MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Heart rate variability: RMSSD | Heart rate variability will be assessed using the root mean square of successive differences (RMSSD), a time-domain measure reflecting parasympathetic (vagal) cardiac modulation. 5 minutes of resting electrocardiogram (ECG) signals will be recorded using BIOPAC systems and processed using Kubios HRV software. | ECG will be collected at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12). In addition, ECG also conducted 14, 48 hours and 2 weeks after the first exercise session or at equivalent times for waitlist participants |
| NIH minimum dataset pain impact stratification subscale | Pain-related impact (pain impact stratification, 9 items 0-50), higher scores indicate greater pain impact on function. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| NIH minimum dataset emotional depression and distress subscale | Pain-related emotional depression and distress (EDD, 4 items 0-16), higher scores indicate greater pain impact on this dimension. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| NIH minimum dataset sleep disturbance subscale | Pain-related sleep disturbance (SlD, 2 items 0-8), higher scores indicate greater pain impact on this dimension. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Oswestry Low Back Pain Disability Index (ODI) | Pain-related disability measured using the Oswestry Low Back Pain Disability Questionnaire (10 items). Each item is scored from 0-5, yielding a total score ranging from 0-50, with higher scores indicating greater disability. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Fatigue severity scale | The Fatigue Severity Scale (FSS) assesses the impact of fatigue on daily functioning. The questionnaire contains 9 items, each rated on a 7-point Likert scale (1-7). Scores are averaged across items, with higher scores indicating greater fatigue severity and functional impairment. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Pittsburgh sleep quality index | The Pittsburgh Sleep Quality Index (PSQI) assesses sleep quality and sleep disturbances over the past month. The instrument contains 19 self-rated items, generating 7 component scores summed into a global score ranging from 0 to 21, with higher scores indicating poorer sleep quality. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Snaith-Hamilton pleasure scale | The Snaith-Hamilton Pleasure Scale (SHAPS) assesses anhedonia (reduced ability to experience pleasure). The scale contains 14 items evaluating pleasure responses to everyday experiences. Total scores range from 0 to 14, with higher scores indicating greater anhedonia. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Multiple abilities self-assessed questionnaire | The Multiple Ability Self-Report Questionnaire (MASQ) assesses self-perceived cognitive functioning in everyday life, including language, memory, attention, and visuospatial abilities. The questionnaire contains 38 items rated on a 5-point Likert scale. Total scores range from 38 to 190, with higher scores indicating greater perceived cognitive difficulties, as well as five subscales for specific cognitive dimensions: Language, Verbal Memory, Visual Memory, Visuo-perceptual Ability, and Attention/Concentration. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Movement-evoked pain | Movement-evoked pain (MeP) will be assessed as the difference between pain at rest and the peak pain intensity reported during or immediately after four movement tasks: balance, sit-to-stand, a tailored provocative movement, and a tailored lifting task. Pain intensity will be rated using a 0-10 Numerical Rating Scale (NRS) before, during and after each task. MeP is calculated with the formula (Peak Pain During/After Task - Pain at Rest), for a score ranging from -10 to +10. An aggregate MeP score will also be calculated as the sum of the score obtained from each task (ranging from -40 to +40). | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Tampa Scale of Kinesiophobia | The Tampa Scale of Kinesiophobia (TSK) assesses fear of movement and injury related to pain. The questionnaire contains 17 items rated on a 4-point Likert scale. Total scores range from 17 to 68, with higher scores indicating greater fear of movement. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Pain Self-Efficacy Questionnaire | The Pain Self-Efficacy Questionnaire (PSEQ) assesses confidence in performing activities despite pain. The questionnaire contains 10 items rated on a 7-point scale (0-6). Total scores range from 0 to 60, with higher scores indicating greater pain self-efficacy. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Beck Depression Inventory | The Beck Depression Inventory-II (BDI-II) assesses severity of depressive symptoms. The instrument contains 21 items rated on a 4-point scale (0-3). Total scores range from 0 to 63, with higher scores indicating greater depressive symptom severity. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| State anxiety inventory | The State Anxiety Inventory (STAI-State) assesses current levels of anxiety. The questionnaire contains 20 items rated on a 4-point scale. Total scores range from 20 to 80, with higher scores indicating greater state anxiety. Data collected in REDCap. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Pressure pain thresholds | Pressure pain thresholds (PPTs) will be measured in kgs using a Wagner FDx algometer. The PPT will be defined as the arithmetic mean of four consecutive measurements taken at two sites bilaterally: (1) the lumbar paraspinal or gluteal muscle, 2 cm lateral to the spinous process or posterior superior iliac spine of the participant's most painful lumbar segment, and (2) the thumbnail bed. | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12) |
| Adverse reactions to physical exercise sessions | After each individual exercise sessions, participants will be asked to complete a short questionnaire to assess whether an adverse reaction to physical exercise (yes/no and details) was experienced. This item will also serve to monitor adherence. Data collected in REDCap. | Immediately after each PE session (Monday, Thursday, and Weekend for 12 weeks) |
| Pain related to physical exercise sessions | After each individual exercise sessions, participants will be asked to complete a short questionnaire to assess pain during and after exercise in a 0-10 NRS. Data collected in REDCap. | Immediately after each PE session (Monday, Thursday, and Weekend for 12 weeks) |
| Effort during physical exercise sessions | After each individual exercise sessions, participants will be asked to complete a short questionnaire to assess effort during the exercise in a 0-100 Borg scale. Data collected in REDCap. | Immediately after each PE session (Monday, Thursday, and Weekend for 12 weeks) |
| Fatigue due to physical exercise sessions | After each individual exercise sessions, participants will be asked to complete a short questionnaire to assess fatigue after exercise in a 0-10 NRS. Data collected in REDCap. | Immediately after each PE session (Monday, Thursday, and Weekend for 12 weeks) |
| 28035017 | Background | Peake JM, Neubauer O, Della Gatta PA, Nosaka K. Muscle damage and inflammation during recovery from exercise. J Appl Physiol (1985). 2017 Mar 1;122(3):559-570. doi: 10.1152/japplphysiol.00971.2016. Epub 2016 Dec 29. |
| 40640567 | Background | Leunig A, Gianeselli M, Russo SJ, Swirski FK. Connection and communication between the nervous and immune systems. Nat Rev Immunol. 2025 Dec;25(12):912-933. doi: 10.1038/s41577-025-01199-6. Epub 2025 Jul 10. |
| 41086330 | Background | Bortsov A, Esfahani SJ, Lima LV, Ji RR, Mogil JS, Diatchenko L. How people resolve pain: insights from human transcriptomics into immune activation and therapeutic innovations. Pain. 2025 Nov 1;166(11S):S60-S64. doi: 10.1097/j.pain.0000000000003671. |
| 24577438 | Background | Grace PM, Hutchinson MR, Maier SF, Watkins LR. Pathological pain and the neuroimmune interface. Nat Rev Immunol. 2014 Apr;14(4):217-31. doi: 10.1038/nri3621. Epub 2014 Feb 28. |
| 34580864 | Background | Hayden JA, Ellis J, Ogilvie R, Malmivaara A, van Tulder MW. Exercise therapy for chronic low back pain. Cochrane Database Syst Rev. 2021 Sep 28;9(9):CD009790. doi: 10.1002/14651858.CD009790.pub2. |
| 22751038 | Background | Baliki MN, Petre B, Torbey S, Herrmann KM, Huang L, Schnitzer TJ, Fields HL, Apkarian AV. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat Neurosci. 2012 Jul 1;15(8):1117-9. doi: 10.1038/nn.3153. |
| 35544595 | Background | Parisien M, Lima LV, Dagostino C, El-Hachem N, Drury GL, Grant AV, Huising J, Verma V, Meloto CB, Silva JR, Dutra GGS, Markova T, Dang H, Tessier PA, Slade GD, Nackley AG, Ghasemlou N, Mogil JS, Allegri M, Diatchenko L. Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Sci Transl Med. 2022 May 11;14(644):eabj9954. doi: 10.1126/scitranslmed.abj9954. Epub 2022 May 11. |
| D012816 | Signs and Symptoms |
| D001519 | Behavior |