Temporal Patterns of Brain Network Plasticity During the Onset and Maintenance of Neuropathic Pain in Male Mice

ABSTRACT Neuropathic pain arises from complex peripheral and central mechanisms and induces long-lasting maladaptive changes in the brain. To investigate the temporal dynamics of these changes, we examined resting-state functional connectivity (FC) in a mouse model of neuropathic pain across its initiation and maintenance phases. Using functional ultrasound imaging to capture whole-brain FC over disease progression, we conducted two complementary studies: a longitudinal assessment in anesthetized animals and an analysis of awake cohorts at distinct disease stages. Both exploratory and literature-guided analyses revealed that FC across most large-scale networks remained remarkably stable during pain maintenance. In contrast, pain onset was marked by enhanced FC between key regions involved in sensory, emotional, and motivational processing, including the motor cortex and nucleus accumbens, the prelimbic and insular cortices, and the infralimbic cortex and hypothalamus. As pain persisted, we observed reduced FC within the somatomotor network, reflecting functional disconnection. Additionally, postsurgical pain alone produced enduring FC changes within the prefrontal cortex, hippocampus, and insula, indicating long-term central plasticity independent of neuropathic injury. Together, these findings reveal dynamic, network-specific adaptations that distinguish the onset and maintenance phases of neuropathic pain and surgery-related plasticity.