Default Mode Network Inflammation as a Supraspinal Mechanism of Pain Chronification

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.

Grant Number: 1F31NS139494-01A1
NIH Institute/Center: NIH
Principal Investigator: Corinne Augusto