Cervical vagus nerve stimulation (VNS) provides relatively minimally-invasive access to vagal fiber populations innervating most visceral organs, making it an attractive therapy candidate for various diseases. To maximize desired and minimize off-target effects, VNS should be delivered in a fiber-selective manner. We sought to select and optimize parameters that preferentially activate large, intermediate or small-size vagal fibers in 2 animal species, rats and mice. We manipulated stimulus

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... form and frequency of short-duration (10-s) stimulus trains (SSTs) at different intensities and measured fiber-specific stimulus-elicited compound action potentials, corresponding cardiorespiratory vagally-mediated responses and neuronal expression of c-FOS in sensory and motor brainstem nuclei. We compiled selectivity indices from those measurements to determine optimal parameters for each fiber type. Large- and intermediate-size fibers are activated by SSTs of 30 Hz frequency, using short-square and long-square or quasi-trapezoidal pulses, respectively, at different optimal intensities for different animals. Small-size fibers are activated by SSTs of frequencies >8KH at high stimulus intensities; using a computational model of vagal fibers we find that sodium channels may underlie this effect. All findings were consistent between rats and mice. Our study provides a robust design and optimization framework for targeting vagal fiber populations for improved safety and efficacy of VNS therapies.