ORIGINAL RESEARCH article
Front. Pain Res.
Sec. Pain Mechanisms
Volume 6 - 2025 | doi: 10.3389/fpain.2025.1548500
Disruptions in Cortical Circuit Connectivity Distinguish Widespread Hyperalgesia from Localized Pain
Provisionally accepted
George Kenefati1,2,3
Mika M. Rockholt1,2,3
Katherine Eisert2
Qiaosheng Zhang1,2,3Deborah Ok1,2,3Christopher G. Gharibo1,2,4Lucia Daiana Voiculescu1,2
Lisa Doan1,2,3
Zhe Sage Chen3,5,6,7
Jing Wang1,2,3,6,7*- 1Langone Medical Center, New York University, New York City, United States
- 2New York University Grossman School of Medicine, Department of Anesthesiology, Perioperative Care and Pain Management, New York, United States
- 3Interdisciplinary Pain Research Program, New York University Grossman School of Medicine, New York, United States
- 4Department of Orthopedics, New York University Grossman School of Medicine, New York, United States
- 5Department of Psychiatry, Grossman School of Medicine, New York University, New York, United States
- 6Department of Neuroscience and Physiology, School of Medicine, New York University, New York, United States
- 7Department of Biomedical Engineering, New York University Tandon School of Engineering, New York, United States
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Widespread hyperalgesia is commonly found in chronic pain conditions, but its mechanisms remain poorly understood. We used stimulus-evoked high-density EEG recordings to investigate interregional functional connectivity in chronic back pain patients with widespread hyperalgesia, patients with localized back pain, or pain-free controls. Compared with controls, chronic pain patients showed altered functional connectivity between regions that process cognitive information and regions the process sensory or affective information. Widespread hyperalgesia, however, is further differentiated from localized pain by decreased inter-hemispheric connectivity of sensory and affective areas and increased intra-hemispheric connectivity between sensory and cognitive cortices. Graph-theoretic further analysis showed that whereas chronic pain is associated with decreased centrality of prefrontal, orbitofrontal, and cingulate areas, widespread hyperalgesia is distinguished by increased centrality of prefrontal and insular areas. Together, our results show that although widespread hyperalgesia shares certain features with localized pain, it is further characterized by distinct cortical mechanisms.
Keywords: Chronic Pain, Chronic low back pain, Pain mechanisms, Pain phenotyping, Hyperalgesia, functional connectivity, EEG
Received: 19 Dec 2024; Accepted: 12 May 2025.
Copyright: © 2025 Kenefati, Rockholt, Eisert, Zhang, Ok, Gharibo, Voiculescu, Doan, Chen and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jing Wang, Interdisciplinary Pain Research Program, New York University Grossman School of Medicine, New York, United States
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