The Functional Anatomy of Nociception: Effective Connectivity in Chronic Pain and Placebo Response

Chronic pain presents a widespread and complex clinical puzzle, necessitating novel theoretical ap­proaches. This study expands upon our evolving comprehension of the brain’s top-down information processing, encompassing functions such as prediction, expectation, and attention, These processes are believed to play a substantial role in shaping both chronic pain and placebo responses. To examine hierarchical cortical processing in pain, we define a minimal cortical pain network comprising the lateral frontal pole, the primary somatosensory cortex, and the posterior insula. Using spectral dynamic causal modeling on resting-state fMRI data we compare effective connectivity among these regions in chronic osteoarthritic patients (n=54, 29F: 25M) and healthy controls (n=18, 10F: 8M) and further analyse dif­ferences between placebo responders and non-responders within the patient group. Our findings reveal distinct patterns of altered top-down, bottom-up, and recurrent (i.e., intrinsic) effective connectivity within the network in chronic pain and placebo response. Specifically, recurrent effective connectivity within the lateral frontal pole becomes more inhibitory, while backward effective connectivity (higher- to-lower cortical regions) decreases in both pain perceivers and placebo responders. Conversely, forward connections exhibit opposite patterns: nociception is associated with more excitatory (disinhibited) con­nections, whereas placebo responses correspond to more inhibitory forward connections. The associated effect sizes were sufficiently large to survive a leave-one-out cross-validation analysis of predictive validity. The observed patterns of alteration are consistent with predictive processing accounts of placebo effects and chronic pain. Overall, effective extrinsic and intrinsic connectivity among cortical regions involved in pain processing emerge as potentially valuable and quantifiable candidate markers of pain perception and placebo response. Significance statement Chronic pain is a widespread and complex healthcare challenge. Cognitive functions such as prediction, expectation, and attention are believed to influence pain perception and placebo responses through top-down information processing in the brain. However, empirical evidence supporting this hypothesis at the brain network level has been lacking. Our study addresses this gap by examining top-down, bottom-up, and recurrent effective connectivity within the brain’s pain processing pathways using resting-state fMRI. We discovered consistent and significant alterations in effective connectivity patterns in chronic pain patients and placebo responders, with the potential to predict individual pain experiences and placebo responses. These findings open new research avenues into the neural mechanisms underlying chronic pain and placebo effects.