High-Frequency Spinal Cord Stimulation Reorganizes Cortical Cross-Frequency Coupling in a Region- and Time-Dependent Manner

Pain management strategies have progressed beyond traditional pharmacologic and physical interventions, integrating advanced neuromodulation techniques such as deep brain stimulation, peripheral nerve stimulation, and high-frequency spinal cord stimulation (hSCS). Despite its clinical efficacy, the supraspinal mechanisms underlying hSCS remain poorly understood. Prior work in sheep demonstrated that hSCS modulates gamma ({gamma}) band (70-150 Hz) activity in the primary somatosensory and association cortices, implicating cortical involvement in pain modulation. Given, the interaction between low and high oscillations, we hypothesized that hSCS modulates {gamma} activity in a region- and time-dependent manner through specific coupling with theta ({square}) rhythms (4-8 Hz). Using 96-channel subdural electrocorticography (ECoG), we computed {square}-{gamma} phase-amplitude coupling (PAC) and the corresponding modulation index (MI) to quantify the effects of hSCS. While the preferred {square}phase of {gamma} activity remained consistent across conditions and regions, MI increased significantly post-stimulation--most prominently in the association cortex, where robust -{gamma} phase locking was observed. In contrast, the somatosensory cortex exhibited weaker and more variable locking. Temporally, both cortices demonstrated an early, rapid increase in MI post-hSCS, accompanied by a shift (association) and attenuation (somatosensory) of the secondary peak. These findings reveal distinct regional and temporal dynamics in PAC following hSCS and suggest complementary roles of somatosensory and association cortices in processing neuromodulatory input. hSCS appears to reorganize cortical cross-frequency interactions, supporting its role in reorganizing functional network dynamics relevant to sensory processing and the subjective pain experience.