ArticlePain reports2025
Neural correlates underlying high-frequency stimulation-induced secondary hyperalgesia in humans.
Article in Pain reports, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Introduction: Central sensitisation (CS), a mechanism that contributes to chronic pain, is partly characterised by increased pain responses to noxious stimuli (hyperalgesia). High-frequency electrical stimulation (HFS) of the skin using surface electrodes is a method to induce CS. Neural correlates of CS induced by HFS are not fully elucidated. Objectives: To characterise neural correlates of HFS-induced CS in healthy humans using functional magnetic resonance imaging to measure brain activity. Methods: Eighteen healthy participants completed magnetic resonance imaging scans before and after onset of HFS-induced hyperalgesia. Scans measured the neural signal during 18 noxious punctate stimuli applied 1 cm outside the HFS site (secondary hyperalgesia area) and during rest. Whole-brain, mixed-effects analysis with correction for multiple comparisons was performed for punctate-evoked neural activity. Whole-brain seed-based functional connectivity analysis was conducted to detect HFS-induced connectivity changes, using periaqueductal grey and nucleus cuneiformis seed regions. Results: High-frequency electrical stimulation induced significant hyperalgesia during punctate stimulation accompanied by increased neural activity in areas involved in pain perception including posterior insula, mid-anterior cingulate cortex, thalamus, and nucleus cuneiformis. Negative functional connectivity between the periaqueductal grey and pain-related cortical regions (insular and secondary somatosensory cortex) was reduced by HFS. Conclusion: Neural correlates of HFS-induced CS are consistent with other experimental CS models such as capsaicin, particularly increased activity of the nucleus cuneiformis - a nucleus of the descending pain modulatory system implicated in human and animal models of CS. Furthermore, changes in functional connectivity between brain regions involved in descending pain modulation suggest a shift toward facilitation over inhibition.
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