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

Abstract

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.