Application of kilohertz-frequency block to mitigate off-target motor effects of vagus nerve stimulation in swine

Selective activation of smaller diameter over large diameter nerve fibers represents a broad challenge in the electrical modulation of neural activity for clinical applications. For example, off-target activation of motor nerve fibers has been implicated in several failed vagus nerve stimulation (VNS) clinical trials by precluding achieving current amplitudes sufficient to activate the therapeutically targeted small diameter fibers. In this study, we evaluated the use of high-frequency (HF) stimulation to block unwanted activation of large diameter fibers evoked by traditional low-frequency (LF) VNS in a large animal (swine) model. We demonstrate that HF can eliminate specific unwanted LF-evoked components from neural recordings with high selectivity – along with their associated off-target physiological responses - while preserving the activation of smaller diameter fibers driving intended physiological responses. Conversely, block of the smaller diameter fibers was only observed at HF amplitudes much higher than amplitudes commonly used for HF block clinically. We found that in addition to blocking the LF-evoked compound action potential, lower HF amplitudes also drive asynchronous activity which can easily be overlooked. Only at high amplitudes did HF block LF-evoked activation without concomitant asynchronous activation. These data have numerous implications for existing and future LF and HF block neuromodulation therapies.