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At day 7, increased (P ≤ 0.01) clustering, node strength, network segregation, and activation of prefrontal-limbic pathways are observed only in the group that develops persistent pain. Later, increased clustering and node strength are more pronounced with persistent pain, particularly within the limbic system, and decrease when pain resolves. Pretreatment with intra-articular etanercept to attenuate pain confirms that these adaptations are associated with pain onset. Results suggest that early and sustained brain changes can differenti