High-Frequency Spinal Cord Stimulation Modifies Tibial Nerve-Stimulation-Evoked Cortical Theta-Gamma Coupling in Sheep Cortex.

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 (γ) 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 γ activity in a region- and time-dependent manner through specific coupling with theta rhythms (θ, 4-8 Hz). To test this, we quantified θ-γ phase-amplitude coupling (PAC) during tibial nerve stimulation (TNS) before (TNS0) and after (TNS1) hSCS to assess cortical processing of TNS-evoked activity, while recording cortical (association and somatosensory cortices) neural activity using 96-channel subdural electrocorticography (ECoG). We then computed the corresponding modulation index (MI) to quantify PAC strength. While the preferred θ phase of γ activity remained consistent across conditions in both cortical areas, θ-γ coupling was more robust and stable in the association than the somatosensory cortex. However, MI increased significantly post-hSCS in both cortices, indicating enhanced θ-γ coupling during TNS1. Temporally, both cortices showed distinct response patterns: the somatosensory cortex exhibited strongest coupling increase early post-hSCS, followed by a progressive decline, whereas the association cortex showed a more delayed and temporally distributed enhancement. These findings indicate that hSCS modulates cortical cross-frequency interactions during TNS-evoked sensory processing, wherein somatosensory and association cortices show distinct temporal coupling dynamics that may contribute to supraspinal mechanisms of pain modulation.