Multimodal characterization of the effects of stimulation on the human brain ex vivo and in vivo.

The underlying mechanisms of therapeutics using brain stimulation in humans are not understood. In particular, it is unknown how brain stimulation impacts gene expression in acute and chronic temporal periods. Although therapeutic approaches like deep brain stimulation are becoming more widely used, it is impossible to study stimulation-induced genetic changes without tissue samples which at best could be collected post-mortem. To overcome these extremely limiting circumstances, we have implemented a multi-part experimental design involving single cell resolution RNA and ATAC sequencing of human cortex that has been stimulated in several paradigms. In the first, acute human cortex slices are stimulated with a high-density microelectrode array, which allows us to track how neural activity changes after stimulation together with genomic changes. In the second, tissue is collected from neurosurgery patients immediately after direct cortical stimulation in vivo. We have uncovered differentially expressed genes and differentially accessible chromatin regions in both paradigms. We have also determined the impact of stimulation on cell assembly plasticity and celltype-specific changes in firing patterns. Our integrated approach of applying stimulation paradigms in human brain tissue both in vivo and ex vivo has not been completed before. These results represent a key first step in our quest to understand exactly how brain stimulation supports neural function at the cellular level.