Electrochemical modulation enhances the selectivity of peripheral neurostimulation in vivo

<jats:title>Significance</jats:title> <jats:p> Bioelectronic medicine relies on electrical stimulation for most applications in the peripheral nervous system. It faces persistent challenges in selectively activating bundled nerve fibers. Here, we investigated ion-concentration modulation with ion-selective membranes and whether this modality may enhance the functional selectivity of peripheral nerve stimulation. We designed a multimodal stimulator that could control Ca <jats:sup>2+</jats:sup> concentrations within a focused volume. Acutely implanting it on the sciatic nerve of a rat, we demonstrated that Ca <jats:sup>2+</jats:sup> depletion could increase the sensitivity of the nerve to electrical stimulation in vivo. We provided evidence that it selectively influenced individual fascicles of the nerve, allowing selective activation by electrical current. Improved functional selectivity may improve outcomes for important therapeutic modalities. </jats:p>