kHz Block Enables Selective Small-Fiber Activation in VNS

by Victor Pikov, contributing editor

April 2025 issue, BioElectRx Business Report

While the main focus of this newsletter is on clinical use of bioelectronic medicine, we occasionally cover animal research that has high clinical potential. Recently, Kip Ludwig’s team at the University of Wisconsin, with assistance from Warren Grill and Nicole Pelot at Duke University, published a preprint of their study, where five pigs were acutely stimulated with two VNS cuffs placed on the cervical vagus. They may have developed a solution toward a holy grail of bioelectronic medicine: small-fiber-selective VNS.

Before going into specifics, it is worth mentioning two important points. First, VNS (and PNS in general) always recruits large fibers first due to intrinsic neurophysiological principles. Second, small-fiber-selective VNS would likely have wide-reaching clinical applications, since it is advantageous to activate only small vagal afferents traveling up to the brainstem while avoiding activating large vagal efferents traveling down, as they can produce detrimental side effects, such as neck muscle activation and slowing of heart rate and breathing.

Since there is no way of bypassing the neurophysiological principle that electrical stimulation activates large fibers first, Ludwig applied a clever trick of crushing their activity with an avalanche of 10,000 pulses per second (compared to 10- to 20 Hz in typical VNS). Such an overwhelming wave of stimulation exhausts the large fibers’ firing capacity and brings them into an inactivated state, a phenomenon known as kHz block. In the meantime, small fibers are slow in responding to kHz pulses, so when they are co-stimulated at low frequency and high amplitude by a second VNS cuff, they are still able to respond, unlike the exhausted large fibers.

It is likely that Ludwig’s approach of exhaustive kHz block of large fibers would work in humans as well, since pig’s vagus size is similar to that of humans. In that case, several clinical opportunities may arise, with the most prominent being VNS therapy for treating heart failure. As described in our July 2024 issue, cervical VNS was previously used in multiple failed clinical trials sponsored by BioControl Medical, Boston Scientific, and LivaNova. While some HF patients benefited, the overall therapeutic efficacy was rather poor as a result of clinician’s inability to apply a high VNS amplitude due to the above-mentioned side effects on the neck muscle, heart rate, and breathing. At the 2021 Neurotech Leaders Forum, Grill offered his insight into the reasons these trials failed, including improper dosing, and inability to stimulate the small-diameter B fibers in the vagus.

The importance of using optimal VNS amplitude was best articulated by a legendary pioneer of this field, Jeff Ardell, who coined the term “neural fulcrum” to indicate a critical balance point of proper VNS dosing. Beyond HF, the idea of achieving “neural fulcrum” with Ludwig’s approach of kHz block might be applied to clinical indications that are already approved by the FDA, such as depression, epilepsy, obesity, and arm rehabilitation after stroke, as well as novel indications, such as rheumatoid arthritis, multiple sclerosis, Crohn’s disease, and other autoimmune diseases.

From the technical point of view, 10 kHz stimulation is not challenging and it is already used by Nevro for treating chronic pain with SCS and by Neuros Medical for treating post-amputation pain with PNS. Repurposing these FDA-approved IPGs could provide researchers and clinicians with a more efficient, faster, and cheaper regulatory pathway for clinical evaluation of various kHz VNS therapies by leveraging existing technology that has already met safety and technical requirements, compared to developing entirely new stimulation devices.