Stimulation modulates cell assemblies linked with gene networks in the human temporal cortex ex vivo

Deep brain stimulation of the temporal cortex can enhance learning and memory in the face of cognitive impairment. Despite the potential of such therapies, the neural and genetic mechanisms underlying the effect of stimulation on human brain circuits are not understood. To explicate direct mechanisms of neural modulation elicited by brain stimulation, we developed an ex vivo approach utilizing microelectrode array stimulation and recording of resected temporal cortex from neurosurgical patients. We find that stimulation preferentially increases firing rates in pyramidal cells compared to interneurons and also strengthens cell assemblies. Using single cell multiomics, we link the observed physiological changes to cell type-specific gene expression patterns. We detail gene regulatory networks that indicate preferential involvement of specific excitatory neuron subtypes and the response of non-neurons. We conclude that the overall impact of stimulation on the human temporal cortex is activation of specific excitatory neurons and enhanced cell assembly activity, and that these changes are supported by gene networks involving immediate early, synaptic, and ion channel genes. Our findings establish a foundation to identify targetable cell type-specific genetic signatures that may be harnessed for therapeutic benefit in future neuromodulation strategies.