Neural correlates underlying high-frequency stimulation-induced secondary hyperalgesia in humans
Published in Pain Reports, 2025
Authors
Sophie Clarke, Vishvarani Wanigasekera, Richard Rogers, Ombretta Caspani, Andre Mouraux, Francesca Fardo, Nanna B. Finnerup, Rolf-Detlef Treede, Irene Tracey.
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.