Neural correlates underlying high-frequency stimulation-induced secondary hyperalgesia in humans

Journal article

IntroductionCentral 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.ObjectivesTo characterise neural correlates of HFS-induced CS in healthy humans using functional magnetic resonance imaging to measure brain activity.MethodsEighteen 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.ResultsHigh-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.ConclusionNeural 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.

Authors: Clarke, S; Wanigasekera, V; Rogers, R; Caspani, O; Mouraux, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Lippincott, Williams & Wilkins
• Journal: PAIN Reports
• Volume: 10
• Issue: 6
• Pages: e1342
• Publication date: 2025-10-15
• Acceptance date: 2025-07-29
• DOI: 10.1097/pr9.0000000000001342
• EISSN: 2471-2531
• ISSN: 2471-2531
• Pmid: 41113663
• Language: English
• Keywords: Functional magnetic resonance imaging (fMRI); Central Sensitisation; High-frequency Stimulation (Hfs); Pain; Experimental Pain Model; Secondary Hyperalgesia