Brain and Gene Expression Responses to Exercise in Chronic Back Pain

Frontostriatal Connectivity and Gene Expression in Exercise-induced Relief of Back Pain

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:

• Supervised exercise training (3 sessions per week, 60 minutes per session, 14 weeks), or
• Wait-list control.

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:

• Resting-state functional MRI
• Diffusion-weighted imaging
• Self-reported pain and disability questionnaires
• Cardiorespiratory and functional testing
• Blood sampling for BDNF and RNA sequencing

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.

Inclusion Criteria:

• Age ≥ 18 years
• Chronic low back pain ≥ 3 months
• Pain present at least half the days over the past 6 months
• Average pain intensity ≥ 3/10 during week prior to enrollment

Exclusion Criteria:

• Diabetes
• Neurological disorder
• Psychiatric disorder
• Significant cardiorespiratory disease
• Under 18 years of age