Electrophysiology of multisite direct electrical stimulation in the human brain

Human cognition and neurological disorders reflect properties of distributed networks, yet how best to engage these networks therapeutically remains unknown. Multisite stimulation is a principled strategy for engaging brain networks, but a key translational barrier is understanding how a network combines concurrent inputs from multiple nodes. Here, we investigated the electrophysiology of simultaneous multisite direct electrical stimulation in 20 participants implanted with stereo-EEG electrodes. Synchronized dual-site stimulation engaged a larger effective network than single-site stimulation. Linear superposition explained most responses, but distinct nonlinear responses were also observed. Sublinear responses, consistent with saturation, occurred proximal to stimulation sites, while supralinear responses arose in network-connected sites during the response's late component. Moreover, low-intensity dual-site stimulation matched or exceeded single-site stimulation at higher intensities. These principles extended to three-site stimulation. These findings systematically characterize how responses to simultaneous multisite stimulation interact in the human brain, a foundational step towards principled, network-guided neurostimulation therapies.