Default Mode Network Inflammation as a Supraspinal Mechanism of Pain Chronification

About This Grant

ABSTRACT A complete understanding of the underlying mechanisms of pain chronification – how temporary acute pain becomes a permanent problem – remains elusive. Pain chronification mechanisms have been explored in the peripheral nervous system and the spinal cord, but the supraspinal mechanisms of chronification are understudied. fMRI is a powerful tool that can detect subtle changes in brain function, including changes in network-level connectivity while at cognitive rest. The Default Mode Network (DMN) is a network that subserves internally directed cognition, deactivating in response to externally directed attentional needs. The DMN has repeatedly been found to have abnormal within-network connectivity in patients with chronic pain. Interestingly, increased intra-DMN connectivity is associated with pain rumination, a psychological symptom of chronic pain similar to the rumination characteristic of Major Depressive Disorder (MDD), a common comorbidity of chronic pain. Abnormal DMN connectivity has been found in patients with MDD, and in people at high risk of developing MDD, suggesting that abnormalities in this network’s connectivity may precede psychological dysfunction. From this, we believe that abnormal DMN connectivity may also precede chronic pain, beginning before acute pain chronifies. We hypothesize that the change in DMN connectivity may be a supraspinal mechanism of pain chronification. This proposal aims to characterize DMN connectivity in a rat model of peripheral nerve injury, examining the rats longitudinally as neuropathic pain progresses. This proposal extends ongoing clinical work seeking connectivity biomarkers predictive of pain chronification in acute musculoskeletal trauma. Additionally, this proposal will explore a potential mechanism of connectivity change: localized neuroinflammation. Multiple brain regions become inflamed after peripheral neuropathic injury, including the prefrontal cortex, hippocampus, and brainstem. It is, therefore, likely that other nodes of the DMN may also experience localized inflammation. This proposal will characterize cytokine and chemokine expression in multiple DMN nodes after peripheral nerve injury to examine the natural inflammatory processes that may occur. Additionally, this proposal will test if microglial silencing in the DMN using site-specific minocycline administration can reverse changes in DMN connectivity and both evoked and spontaneous pain behaviors. Collectively, these results will provide foundational data on the significance of inflammatory processes in the DMN, and of intra-DMN connectivity more broadly, to the propagation of pain after peripheral nerve injury, justifying future longitudinal clinical studies and providing new targets for the prevention of pain chronification.