Neuroimmune Responses to Exercise in Chronic Back Pain

Official title

Neuroimmune Responses to Physical Exercise Training in Chronic Primary Low Back Pain

Overview

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.

Detailed description

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.

Interventions

• Behavioral Physical Exercise
  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.

Primary outcome measures

• Chronic Low Back Pain Intensity [Time frame: Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12). In addition, assessed daily through electronic pain diaries.]

Secondary outcome measures (12)

• Peripheral Blood Gene Expression (RNA Sequencing) [Time frame: 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]
• Nucleus Accumbens-Medial Prefrontal Cortex Functional Connectivity [Time frame: MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12)]
• Fractional Anisotropy of NAc-mPFC White Matter Tract [Time frame: MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12)]
• Whole-Brain Intrinsic Connectivity [Time frame: MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12)]
• Tonic Pain Signature (ToPS) [Time frame: MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12)]
• Nociplastic Functional Signature (NFS) [Time frame: MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12)]
• Hippocampal volume [Time frame: MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12)]
• Superior Longitudinal Fasciculus (SLF) White Matter Integrity [Time frame: MRI acquired at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12)]
• Heart rate variability: RMSSD [Time frame: 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 [Time frame: Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12)]
• NIH minimum dataset emotional depression and distress subscale [Time frame: Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12)]
• NIH minimum dataset sleep disturbance subscale [Time frame: Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12)]

Eligibility criteria

Inclusion Criteria-CLBP patients:

• Have a diagnosis of chronic primary LBP, according to the criteria established by NIH Task Force on Research Standards for CLBP (Deyo et al., 2015). This will be determined by 1) the response to the National Institutes of Health minimum dataset for CLBP (NIH-md), including that LBP has been persistent for at least 3 months or recurrent for at least half of the days in the past 6 months, and 2) the results of a complete case history and physical examination (including functional tasks, quantitative sensory testing, and, if needed, neuro-orthopedic, palpation and range of motion assessments);
• Report a CLBP intensity of at least 4 in a 0-10 numerical rating scale (0 = no pain, 10 = maximum possible pain).

Inclusion Criteria-Healthy controls:

\- Be over 18 years and under 75 years of age;

Exclusion Criteria-CLBP patients:

• Present any red flags indicative of serious pathology comorbid or as the cause of CLBP (Finucane et al., 2020);
• Have a CLBP phenotype characterized by predominant nociceptive (as in fracture, infection, malignancy, inflammatory or rheumatic spondyloarthropathy, cauda equina syndrome, confirmed by MRI when suspected) or neuropathic pain mechanisms, the latter assessed through score in the DN4 questionnaire (Nijs, et al., 2024);
• Present chronic or acute pain of higher intensity or perceived disability in any other body site than the low back;
• Medical history of diabetes, neurological or psychiatric disorder;
• Presence of significant cardiorespiratory problems or any other potential contraindications to physical exercise as assessed through the Physical Activity Readiness Questionnaire for Everyone (PAR-Q+);
• Following a regular structured PE training program (>60 min/week) at study's onset, and;
• Presence of any contraindications to MRI examination (including any metallic implants or devices, being pregnant, and claustrophobia).

Exclusion criteria-Healthy controls:

• Have symptoms or a diagnosis of any acute or chronic pain conditions;
• Medical history of diabetes, neurological or psychiatric disorder;
• Presence of significant cardiorespiratory problems or any other potential contraindications to physical exercise as assessed through the Physical Activity Readiness Questionnaire for Everyone (PAR-Q+);
• Following a regular structured PE training program (>60 min/week) at study's onset, and;
• Presence of any contraindications to MRI examination (including any metallic implants or devices, being pregnant, and claustrophobia).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Basic science

Study locations

Canada · 1 center

• Montreal General Hospital — Montreal

Publications

• 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. PMID 38755449
• 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. PMID 38670108
• 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. PMID 28035017
• 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. PMID 40640567
• 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. PMID 41086330
• 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. PMID 24577438
• 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. PMID 34580864
• 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. PMID 22751038

Identifiers

NCT: NCT07497425 · eCLBP

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗