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

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.