Bipolar intracortical microstimulation expands the repertoire of neuronal activation patterns

Objective: Intracortical microstimulation is a promising approach for sensory restoration, but its spatial selectivity and variability of human perception are constrained by current spread and electrode configuration. We investigated how varying the return-electrode position during intracortical bipolar stimulation influences the spatial distribution and composition of activated neuronal populations. Approach: We combined two-photon calcium imaging in acute mouse cortical slices with biophysically grounded computational modeling to characterize neuronal activation at the cellular and population level. We applied bipolar stimulation across a range of electrode configurations, systematically varying current direction, electrode spacing, and stimulation parameters. Main results: Bipolar stimulation activated distinct neuronal populations depending on electrode configuration, with activation patterns becoming less overlapping as the angular difference between stimulation directions increased. Population-level analyses revealed a small number of dominant activation patterns across stimulation configurations. Electrode spacing influenced both the number of activated neurons and the spatial extent of activation, whereas polarity and waveform asymmetry had comparatively modest effects. Computational modeling indicated that bipolar activation predominantly reflected the combined effect of the two corresponding monopolar stimulations, with an additional bipolar-specific component. Neurons activated exclusively by bipolar stimulation were relatively sparse and spatially dispersed. Significance: Our findings demonstrate that varying bipolar electrode configurations produces distinct patterns of neuronal activation, providing an additional mode for recruiting different neural populations. Computational modeling suggests that these patterns largely reflect the combined contributions of the individual electrodes, with additional differences which may reflect non-linear neuronal or network interactions. Together, these findings provide insight into how the electrode configuration shapes cortical activation patterns and how intracortical bipolar stimulation provides additional ways to activate neuronal populations without increasing electrode density.