Neuroimmune Responses to Exercise in Chronic Back Pain

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.

Gene expression levels assessed in peripheral blood using RNA sequencing. Transcriptomic analyses evaluated differential gene expression and pathway analyses.

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.

Fractional Anisotropy (FA) measured using diffusion-weighted imaging (DWI) probabilistic tractography along the white matter connecting the nucleus accumbens and medial prefrontal cortex.

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.

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.

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.

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.

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.

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.

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

Pain-related emotional depression and distress (EDD, 4 items 0-16), higher scores indicate greater pain impact on this dimension. Data collected in REDCap.

Pain-related sleep disturbance (SlD, 2 items 0-8), higher scores indicate greater pain impact on this dimension. Data collected in REDCap.

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. Data collected in REDCap.

The Fatigue Severity Scale (FSS) assesses the impact of fatigue on daily functioning. The questionnaire contains 9 items, each rated on a 7-point Likert scale (1-7). Scores are averaged across items, with higher scores indicating greater fatigue severity and functional impairment. Data collected in REDCap.

The Pittsburgh Sleep Quality Index (PSQI) assesses sleep quality and sleep disturbances over the past month. The instrument contains 19 self-rated items, generating 7 component scores summed into a global score ranging from 0 to 21, with higher scores indicating poorer sleep quality. Data collected in REDCap.

The Snaith-Hamilton Pleasure Scale (SHAPS) assesses anhedonia (reduced ability to experience pleasure). The scale contains 14 items evaluating pleasure responses to everyday experiences. Total scores range from 0 to 14, with higher scores indicating greater anhedonia. Data collected in REDCap.

The Multiple Ability Self-Report Questionnaire (MASQ) assesses self-perceived cognitive functioning in everyday life, including language, memory, attention, and visuospatial abilities. The questionnaire contains 38 items rated on a 5-point Likert scale. Total scores range from 38 to 190, with higher scores indicating greater perceived cognitive difficulties, as well as five subscales for specific cognitive dimensions: Language, Verbal Memory, Visual Memory, Visuo-perceptual Ability, and Attention/Concentration. Data collected in REDCap.

Movement-evoked pain (MeP) will be assessed as the difference between pain at rest and the peak pain intensity reported during or immediately after four movement tasks: balance, sit-to-stand, a tailored provocative movement, and a tailored lifting task. Pain intensity will be rated using a 0-10 Numerical Rating Scale (NRS) before, during and after each task. MeP is calculated with the formula (Peak Pain During/After Task - Pain at Rest), for a score ranging from -10 to +10. An aggregate MeP score will also be calculated as the sum of the score obtained from each task (ranging from -40 to +40).

The Pain Catastrophizing Scale (PCS) assesses catastrophic thinking related to pain, including rumination, magnification, and helplessness. The scale contains 13 items rated on a 5-point scale (0-4). Total scores range from 0 to 52, with higher scores indicating greater pain catastrophizing. Data collected in REDCap.

The Tampa Scale of Kinesiophobia (TSK) assesses fear of movement and injury related to pain. The questionnaire contains 17 items rated on a 4-point Likert scale. Total scores range from 17 to 68, with higher scores indicating greater fear of movement. Data collected in REDCap.

The Pain Self-Efficacy Questionnaire (PSEQ) assesses confidence in performing activities despite pain. The questionnaire contains 10 items rated on a 7-point scale (0-6). Total scores range from 0 to 60, with higher scores indicating greater pain self-efficacy. Data collected in REDCap.

The Beck Depression Inventory-II (BDI-II) assesses severity of depressive symptoms. The instrument contains 21 items rated on a 4-point scale (0-3). Total scores range from 0 to 63, with higher scores indicating greater depressive symptom severity. Data collected in REDCap.

The State Anxiety Inventory (STAI-State) assesses current levels of anxiety. The questionnaire contains 20 items rated on a 4-point scale. Total scores range from 20 to 80, with higher scores indicating greater state anxiety. Data collected in REDCap.

Pressure pain thresholds (PPTs) will be measured in kgs using a Wagner FDx algometer. The PPT will be defined as the arithmetic mean of four consecutive measurements taken at two sites bilaterally: (1) the lumbar paraspinal or gluteal muscle, 2 cm lateral to the spinous process or posterior superior iliac spine of the participant's most painful lumbar segment, and (2) the thumbnail bed.

After each individual exercise sessions, participants will be asked to complete a short questionnaire to assess whether an adverse reaction to physical exercise (yes/no and details) was experienced. This item will also serve to monitor adherence. Data collected in REDCap.

After each individual exercise sessions, participants will be asked to complete a short questionnaire to assess pain during and after exercise in a 0-10 NRS. Data collected in REDCap.

After each individual exercise sessions, participants will be asked to complete a short questionnaire to assess effort during the exercise in a 0-100 Borg scale. Data collected in REDCap.

After each individual exercise sessions, participants will be asked to complete a short questionnaire to assess fatigue after exercise in a 0-10 NRS. Data collected in REDCap.