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| Name | Class |
|---|---|
| Canadian Institutes of Health Research (CIHR) | OTHER_GOV |
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This study is registered retrospectively for transparency. This mechanistic randomized controlled trial examined whether a 14-week supervised physical exercise training program reduces chronic low back pain (CLBP) by modulating frontostriatal brain connectivity and immune-related gene expression. Fifty-seven adults with CLBP were randomized to exercise training or wait-list control. Participants underwent pre- and post-intervention MRI, questionnaires, and blood sampling. The study tested whether reductions in nucleus accumbens-medial prefrontal cortex connectivity and changes in inflammatory gene expression mediated exercise-induced pain relief.
Chronic low back pain (CLBP) is associated with altered functional connectivity between the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), as well as systemic low-grade inflammation.
This mechanistic randomized controlled trial evaluated the effects of a 14-week supervised physical exercise (PE) training program on pain intensity, functional disability, brain connectivity, and peripheral gene expression in individuals with CLBP.
Participants were randomized to either:
Exercise sessions combined aerobic and resistance training. Exercise intensity was individually calibrated based on VO2max and 1 repetition maximum (1RM) assessments.
Assessments conducted pre- and post-intervention included:
The primary mechanistic hypothesis tested whether changes in NAc-mPFC connectivity and immune-related gene expression mediated exercise-induced reductions in chronic pain. Therefore, primary outcomes focused on indices of target engagement (including immune gene expression and brain connectivity) rather than clinical efficacy alone.
Note: This study was not registered prior to participant enrolment. The project was investigator-initiated and conceived as a mechanistic investigation prior to widespread mandatory registration requirements. Study recruitment and progress were also substantially influenced by the COVID-19 pandemic and associated lockdowns.
The clinical efficacy of PE for CLBP is already well established. Consequently, the primary aim of the present study was to examine the biological mechanisms through which PE may influence pain. Registration is therefore being completed retrospectively to ensure transparency.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active intervention | Experimental | Physical exercise training |
|
| Waitlist control | No Intervention | Participants underwent all assessments but did not receive exercise training during the 14-week study period. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Supervised physical exercise training | Behavioral | 60-minute sessions 3 times weekly Aerobic + resistance training Individually calibrated intensity (VO2max, 1RM) Total duration: 14 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Chronic Low Back Pain Intensity | Self-reported average low back pain intensity measured using an 11-point Numerical Rating Scale (NRS; 0-10), where 0 = "no pain" and 10 = "worst imaginable pain." | Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 14) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Assessed at Baseline (Week 0) and Post-intervention (Week 14) |
| Measure | Description | Time Frame |
|---|---|---|
| Submaximal Aerobic Power (subMAP85%) | Submaximal aerobic power assessed during a graded exercise test at 85% of estimated maximal capacity. Measured in watts (W). | Assessed at Baseline (Week 0) and Post-intervention (Week 14) |
| Six-Minute Walk Distance |
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centre de Recherche de l'Institut Universitaire de Gériatrie de Montréal | Montreal | Quebec | H3W 1W4 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38961071 | Background | Hird EJ, Slanina-Davies A, Lewis G, Hamer M, Roiser JP. From movement to motivation: a proposed framework to understand the antidepressant effect of exercise. Transl Psychiatry. 2024 Jul 4;14(1):273. doi: 10.1038/s41398-024-02922-y. | |
| 40173244 | Background | Jiang R, Geha P, Rosenblatt M, Wang Y, Fu Z, Foster M, Dai W, Calhoun VD, Sui J, Spann MN, Scheinost D. The inflammatory and genetic mechanisms underlying the cumulative effect of co-occurring pain conditions on depression. Sci Adv. 2025 Apr 4;11(14):eadt1083. doi: 10.1126/sciadv.adt1083. Epub 2025 Apr 2. |
| Label | URL |
|---|---|
| Study pre-print | View source |
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| ID | Term |
|---|---|
| D059350 | Chronic Pain |
| D001416 | Back Pain |
| D009043 | Motor Activity |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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Mechanistic trial
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| Nucleus Accumbens-Medial Prefrontal Cortex Functional Connectivity |
Functional connectivity assessed using resting-state functional magnetic resonance imaging (rsfMRI). Seed-to-voxel analyses were performed using anatomically defined bilateral nucleus accumbens and medial prefrontal cortex regions. |
| MRI acquired at Baseline (Week 0) and Post-intervention (Week 14) |
| Whole-Brain Intrinsic Connectivity | Intrinsic connectivity analysis (voxel-wise network centrality; root mean square of all connections) performed using resting-state fMRI. | MRI acquired at Baseline (Week 0) and Post-intervention (Week 14) |
| Fractional Anisotropy of NAc-mPFC White Matter Tract | Fractional Anisotropy (FA) measured using diffusion-weighted imaging (DWI) probabilistic tractography along the white matter tract connecting the nucleus accumbens and medial prefrontal cortex. | MRI acquired at Baseline (Week 0) and Post-intervention (Week 14) |
| Peripheral Blood Gene Expression (RNA Sequencing) | Gene expression levels assessed in peripheral blood immune cells using RNA sequencing (DESeq2 analysis). Transcriptomic analyses evaluated differential gene expression and pathway enrichment. | Blood samples collected prior to Session 7 (first calibrated-intensity session, Week 3) and prior to Session 42 (final session, Week 14) |
| Plasma Brain-Derived Neurotrophic Factor (BDNF) | Plasma BDNF concentrations measured using Luminex multiplex assay (Human ProcartaPlex). The purpose of this outcome is to evaluate both acute and longer-term neurotrophic responses to exercise training. Acute changes were measured before and after high-intensity training sessions; long-term changes were assessed by comparing baseline levels across sessions. | Collected immediately before and after Session 7 (Week 3) and immediately before and after Session 42 (Week 14) |
Functional exercise capacity measured using the 6-Minute Walk Test (6MWT). Distance walked in meters during 6 minutes was recorded.
| Assessed at Baseline (Week 0) and Post-intervention (Week 14) |
| 28087891 | Background | Geneen LJ, Moore RA, Clarke C, Martin D, Colvin LA, Smith BH. Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2017 Jan 14;1(1):CD011279. doi: 10.1002/14651858.CD011279.pub2. |
| 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. |
| 37179769 | Background | Lesnak JB, Berardi G, Sluka KA. Influence of routine exercise on the peripheral immune system to prevent and alleviate pain. Neurobiol Pain. 2023 Mar 21;13:100126. doi: 10.1016/j.ynpai.2023.100126. eCollection 2023 Jan-Jul. |
| 25082697 | Background | Schwartz N, Temkin P, Jurado S, Lim BK, Heifets BD, Polepalli JS, Malenka RC. Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens. Science. 2014 Aug 1;345(6196):535-42. doi: 10.1126/science.1253994. |
| 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. |
| D001519 | Behavior |
| D010335 | Pathologic Processes |