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Seed-based functional connectivity of the anterior cingulate cortex and the posterior insula predicts placebo analgesia in Parkinson’s disease
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DOI：10.1038/s41598-026-64622-5.png)
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Abstract
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Chronic pain affects up to 80% of people with Parkinson’s disease (PD) and remains difficult to treat. Functional brain connectivity can predict analgesic response in other conditions, but has not been explored in PD. To assess whether baseline resting-state functional connectivity predicts placebo-induced pain relief in PD patients with chronic pain. We analysed clinical and resting-state fMRI data from two randomized controlled trials. Sixty-six PD participants with pain (mean age 65 ± 7 years; disease duration 7 ± 4 years; 48% women; VAS 57.5 ± 15.8) received either high-dose levodopa, oxycodone, placebo (OXYDOPA), or foot reflexology, sham massage (DOREPAR). None of the trials demonstrated an analgesic effect compared to the control group. Baseline connectivity was compared between improved patients (defined as showing ≥ 30% reduction in mean pain intensity (VAS) after treatment) and non-improved patients using two-sample t-tests. It was also correlated to the reduction of the mean VAS in percentage using Spearman correlations. Seed-to-voxel and ROI-to-ROI analyses were employed on regions implicated in analgesic response: anterior cingulate cortex (ACC), insula, medial prefrontal and middle frontal gyri. Twenty-six participants were classified as improved. Compared to non-improved, they showed stronger baseline connectivity between the ACC and a cluster in the posterior cingulate cortex and paracentral lobule (0.30 ± 0.11 vs. 0.13 ± 0.14; mean difference [0.102; 0.228]). Pain reduction was associated with more negative connectivity between the right posterior insula and a right superior frontal/frontal pole cluster (rho = − 0.528, p < 0.01). Specific functional connectivity patterns in brain regions involved in the contextual and cognitive modulation of pain may predict placebo-induced pain relief in PD.
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