Characterizing neuronal and population responses to electrical stimulation in the human hippocampo-cortical network.

BACKGROUND: The hippocampus is a common target for direct electrical stimulation (DES). While considerable research has focused on clinical outcomes of various stimulation protocols, the precise neural dynamics of DES in the human hippocampus remain poorly understood, limiting our ability to model and predict hippocampal neural activity. Conventional stereotactic electrodes provide limited insight as the recorded signal becomes saturated during DES, allowing to only record LFP activity from stimulation in sufficiently distant areas. Behnke-Fried electrodes circumvent this limitation, enabling simultaneous recording of local hippocampal single-unit and LFP activity during stimulation. OBJECTIVE: We aimed to characterize the neural responses to single pulse DES in the hippocampus and surrounding cortical areas at both single-neuron and population levels. METHODS: We collected data from 34 hippocampally implanted Behnke-Fried electrodes across seven epilepsy patients. This unique approach allowed us to monitor both local field potentials and single neuron activity (N = 136) in response to 1 ms bipolar single pulse DES in the hippocampus and surrounding neocortex. Single pulses were administered systematically across electrode leads terminating in the neocortex, allowing us to assess both local responses and network propagation effects. RESULTS: Despite high stimulation intensity, only 29 % of single units exhibited measurable responses to hippocampal stimulation. Responsive neurons displayed a stereotypical pattern: an initial excitatory response (cluster size: 110 ms, p = 0.0017) followed by an inhibitory 'silent period' of reduced firing (cluster size: 141 ms, p < 0.0005). Both the intensity of the initial excitation and the duration of the silent period were inversely correlated with distance from the stimulation site (peak height: r = -0.94, p < 0.0001; silent duration: r = -0.93, p < 0.0001). LFP responses corroborated these findings in both time and frequency domains. Notably, hippocampal responses to neocortical stimulation revealed a consistent lag of approximately 100 ms. Finally, we found evidence that cortical responses to hippocampal stimulation were modulated by hippocampal theta phase at the time of stimulation. CONCLUSIONS: We provide the first comprehensive characterization of hippocampal responses to DES at both neuronal and population levels in the human hippocampo-cortical network. Our findings of stereotypical response patterns and quantifiable phase-dependent network effects provide crucial parameters to inform future stimulation paradigms targeting the human memory system.