Neuroimmune Responses to Exercise in Chronic Back Pain

McGill University216 enrolled

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.

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.

Conditions

Chronic Low Back Pain (CLBP)

Interventions

Physical ExerciseBEHAVIORAL

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 YearsHealthy volunteers:

Medical Language ↔ Plain English

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).

Locations (1)

Montreal General Hospital

Montreal, Quebec, Canada

RECRUITING

Outcomes

Primary Outcomes

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.

Time frame: Assessed at Baseline (Pre-intervention, Week 0) and Post-intervention (Week 12). In addition, assessed daily through electronic pain diaries.

Secondary Outcomes

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.

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

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.

Time frame: 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.

Time frame: 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.

Central Contacts

Carlos Gevers Montoro, PhD

CONTACT

+1-8199790448 carlos.geversmontoro@mcgill.ca

Data from ClinicalTrials.gov

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Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Enrollment

216

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

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

Pain-related impact (pain impact stratification, 9 items 0-50), higher scores indicate greater pain impact on function. Data collected in REDCap.