Reshaping cortical circuits through stimulation represents an emerging therapy for the restoration of cognitive function1–5, yet the biological mechanisms that underlie its effects remain largely unexplored in humans. Here, to directly investigate the mechanisms of neuromodulation elicited by human brain stimulation, we developed an ex vivo platform that integrates microelectrode array stimulation with simultaneous recording and single-nucleus genomics from resected temporal cortex obtained from patients undergoing neurosurgery. We found that stimulation strengthens cell assemblies and then linked this effect to cell-type-specific gene regulatory networks. We further demonstrated the generalizability of these findings by identifying common cell-type-specific gene expression signatures in the human cortex following in vivo stimulation. Together, our results establish a foundation for identifying targetable genetic signatures linked with physiology that may be harnessed for therapeutic benefit via neuromodulation strategies.
