Large-scale functional brain network organization is largely preserved in neuropathic pain despite selective circuit-level adaptations
Abstract
Neuropathic pain results from damage to the nervous system and causes persistent changes in brain function that contribute to chronic pain. Understanding how these changes evolve over time is essential for identifying the mechanisms that sustain the disease. Here we show how brain-wide communication changes during the development and persistence of neuropathic pain in male mice using resting-state functional ultrasound imaging in awake and anesthetized animals. Pain onset is associated with transient increases in communication between brain regions involved in sensory, motivational, and emotional processing, whereas the persistent phase shows reduced communication within movement-related networks. Animals that undergo surgery without nerve injury also display lasting changes, revealing brain plasticity independent of neuropathic pain. Despite these network alterations, the overall organization of spontaneous brain activity remains stable. These findings reveal phase-dependent adaptations in brain circuits while preserving global resting-state brain dynamics.Pain is defined as an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage, and it often arises from a lesion or disease affecting the somatosensory system. Neuropathic pain represents a significant global health burden, affecting 7-10% of the population 1 . In this condition, lesioned sensory neurons transmit abnormal signals to the spinal cord and brain, producing characteristic symptoms, such as allodynia and hyperalgesia 2 . Over time, this altered signaling induces long-lasting central sensitization, leading to widespread electrophysiological, structural, and functional changes across various brain regions 3 .
These brain regions are often part of broader functional networks that serve multiple roles beyond pain perception, including emotional regulation and cognitive control. For instance, the cingulate cortex and the prefrontalamygdala axis are critically involved in both nociception and mood regulation. This overlap has led to the hypothesis that maladaptive plasticity in these hubs may underlie the high comorbidity of chronic pain with affective disorders, such as anxiety and depression 4 . While many studies have identified the brain regions activated during acute pain (often referred to as the 'pain matrix'), much less is known about how brain networks reorganize as pain becomes chronic. Pioneering work by Apkarian and colleagues revealed that functional connectivity (FC) between the nucleus accumbens (NAc) and other limbic and cortical structures could predict the transition to chronic pain in humans 5 , suggesting that network-level biomarkers may play a central role in pain chronification.
Resting-state functional connectivity has emerged as a promising approach for studying such brain-wide alterations. This method captures spontaneous fluctuations in neural activity, offering insights into the intrinsic organization of the brain and its longitudinal dynamics in both humans and animals 6-8 . In preclinical models, it allows researchers to track neural adaptations in controlled environments and over defined disease stages.
Although most resting-state studies rely on static FC measures averaged over the entire recording period, spontaneous brain activity is increasingly recognized as dynamically organized into recurring functional.
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BibTeX
@article{cazzanelli2026largescale,
title = {{Large-scale functional brain network organization is largely preserved in neuropathic pain despite selective circuit-level adaptations}},
author = {Silvia Cazzanelli and Samuel Le Meur-Diebolt and Jérome Baranger and Youenn Travert-Jouanneau and Luc Eglin and Ipek Yalcin and Adrien Bertolo and Alexandre Dizeux and Nathalie Ialy-Radio and Thomas Deffieux and Mickael Tanter and Bruno Felix Osmanski and Jeremy Ferrier and Sophie Pezet},
journal = {Communications Biology},
year = {2026},
month = sep,
doi = {10.1038/s42003-026-10922-5},
url = {https://hal.science/hal-05767276v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Large-scale functional brain network organization is largely preserved in neuropathic pain despite selective circuit-level adaptations
AU - Silvia Cazzanelli
AU - Samuel Le Meur-Diebolt
AU - Jérome Baranger
AU - Youenn Travert-Jouanneau
AU - Luc Eglin
AU - Ipek Yalcin
AU - Adrien Bertolo
AU - Alexandre Dizeux
AU - Nathalie Ialy-Radio
AU - Thomas Deffieux
AU - Mickael Tanter
AU - Bruno Felix Osmanski
AU - Jeremy Ferrier
AU - Sophie Pezet
PY - 2026
DA - 2026/09/23
JO - Communications Biology
DO - 10.1038/s42003-026-10922-5
UR - https://hal.science/hal-05767276v1
AB - Neuropathic pain results from damage to the nervous system and causes persistent changes in brain function that contribute to chronic pain. Understanding how these changes evolve over time is essential for identifying the mechanisms that sustain the disease. Here we show how brain-wide communication changes during the development and persistence of neuropathic pain in male mice using resting-state functional ultrasound imaging in awake and anesthetized animals. Pain onset is associated with transient increases in communication between brain regions involved in sensory, motivational, and emotional processing, whereas the persistent phase shows reduced communication within movement-related networks. Animals that undergo surgery without nerve injury also display lasting changes, revealing brain plasticity independent of neuropathic pain. Despite these network alterations, the overall organization of spontaneous brain activity remains stable. These findings reveal phase-dependent adaptations in brain circuits while preserving global resting-state brain dynamics.Pain is defined as an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage, and it often arises from a lesion or disease affecting the somatosensory system. Neuropathic pain represents a significant global health burden, affecting 7-10% of the population 1 . In this condition, lesioned sensory neurons transmit abnormal signals to the spinal cord and brain, producing characteristic symptoms, such as allodynia and hyperalgesia 2 . Over time, this altered signaling induces long-lasting central sensitization, leading to widespread electrophysiological, structural, and functional changes across various brain regions 3 . These brain regions are often part of broader functional networks that serve multiple roles beyond pain perception, including emotional regulation and cognitive control. For instance, the cingulate cortex and the prefrontalamygdala axis are critically involved in both nociception and mood regulation. This overlap has led to the hypothesis that maladaptive plasticity in these hubs may underlie the high comorbidity of chronic pain with affective disorders, such as anxiety and depression 4 . While many studies have identified the brain regions activated during acute pain (often referred to as the 'pain matrix'), much less is known about how brain networks reorganize as pain becomes chronic. Pioneering work by Apkarian and colleagues revealed that functional connectivity (FC) between the nucleus accumbens (NAc) and other limbic and cortical structures could predict the transition to chronic pain in humans 5 , suggesting that network-level biomarkers may play a central role in pain chronification. Resting-state functional connectivity has emerged as a promising approach for studying such brain-wide alterations. This method captures spontaneous fluctuations in neural activity, offering insights into the intrinsic organization of the brain and its longitudinal dynamics in both humans and animals 6-8 . In preclinical models, it allows researchers to track neural adaptations in controlled environments and over defined disease stages. Although most resting-state studies rely on static FC measures averaged over the entire recording period, spontaneous brain activity is increasingly recognized as dynamically organized into recurring functional.
SN - 2399-3642
ER -