Theta-Gamma Phase-Amplitude Coupling in the Dynamic Pain Connectome in Healthy Individuals and Abnormalities in People with Chronic Pain

The experience of pain arises from spontaneous, dynamic activity within and between multiple brain regions, but the interaction underlying these patterns of communication and coordination are not well understood. Phase-amplitude coupling (PAC) of theta and gamma oscillations reflects complex interactions possibly involved in nociceptive processing and modulation at different points of interaction within the dynamic pain connectome (DPC) in the ascending nociceptive (Asc) and descending antinociceptive (Desc) pathways, default mode (DMN) and salience networks (SN). This study investigated whether PAC of intrinsic activity within the DPC is normally present and/or disrupted in people with chronic pain. We analyzed a previously published dataset to measure theta-gamma PAC in the DPC from resting-state magnetoencephalography in 38 healthy individuals (HCs: 20 M, 18 F) and 37 people with chronic pain associated with ankylosing spondylitis (20 M, 17 F). We also examined whether PAC was associated with chronic pain intensity, disease severity, and functional limitations. We found that over 80% of all individuals exhibited PAC in main regions of the Asc, SN, and DMN but was less common (<45% of individuals) in the right subgenual anterior cingulate and left posterior cingulate cortices. Furthermore, PAC in the right midcingulate cortex was significantly decreased in individuals with chronic pain compared to HCs, and, in females with chronic pain, was correlated to functional limitations with a medium effect size. These novel findings implicate theta-gamma PAC as a means to shape nociceptive brain processes and point to PAC failures as a possible mechanistic contributor to chronic pain.