Intracortical Microstimulation Induces Rapid Microglia Process Convergence

Intracortical microstimulation (ICMS) can generate useful percepts to restore vision and hearing when applied to the relevant regions of cortex in animals and humans and has great clinical translational potential for sensory restoration. The neuronal response to ICMS has been extensively studied at the cellular level through electrophysiology and 2-photon (2P) imaging studies. The response of non-neuronal cells and in particular of microglia, as well as the effects of ICMS on blood brain barrier (BBB) integrity, have yet to be understood. Here, we applied ICMS under 2P imaging in dual reporter mice expressing green fluorescent protein in microglia and red fluorescent Ca+ indicator in neurons. We also imaged vascular dye leakage to monitor BBB integrity throughout the experiment. We used clinically relevant waveform parameters and tested a range of current amplitudes. We found that, surprisingly, microglia respond rapidly within 15 minutes following stimulation via microglia process convergence (MPC) on areas of particularly high neural activity. The prevalence of MPC increased as current amplitude increased, but interestingly, it did not bear a relationship to the strength of the local electric field. Vascular dye penetration into the tissue was higher for stimulated than unstimulated control animals and increased as ICMS current amplitude increased. Taken together, these results demonstrate a more rapid and active microglia and BBB response to ICMS than previously thought and highlight the need for future studies to understand the full biological response to ICMS and establish safety standards.