Modulating functionally-distinct vagus nerve fibers using microelectrodes and kilohertz frequency electrical stimulation.

Modulation of functionally distinct nerve fibers with bioelectronic devices provides a therapeutic opportunity for various diseases. In this study, we began by developing a computational model including four major subtypes of myelinated fibers and one unmyelinated fiber. Second, we used an intrafascicular electrode to perform kHz-frequency electric stimulation to preferentially modulate a population of fibers. Our model suggests that fiber physical properties and electrode-to-fascicle distance severely impacts stimulus-response relationships. Large diameter fibers (Aα- and Aß-) were only minimally influenced by the fascicle size and electrode location, while smaller diameter fibers (Aδ-, B- and C-) indicated a stronger dependency.Clinical Relevance- Our findings support the possibility of selectively modulating functionally-distinct nerve fibers using electrical stimulation in a small, localized region. Our model provides an effective tool to design next-generation implantable devices and therapeutic stimulation strategies toward minimizing off-target effects.

kHz-frequency electrical stimulation selectively activates small, unmyelinated vagus afferents.

BACKGROUND: Vagal reflexes regulate homeostasis in visceral organs and systems through afferent and efferent neurons and nerve fibers. Small, unmyelinated, C-type afferents comprise over 80% of fibers in the vagus and form the sensory arc of autonomic reflexes of the gut, lungs, heart and vessels and the immune system. Selective bioelectronic activation of C-afferents could be used to mechanistically study and treat diseases of peripheral organs in which vagal reflexes are involved, but it has not been achieved. METHODS: We stimulated the vagus in rats and mice using trains of kHz-frequency stimuli. Stimulation effects were assessed using neuronal c-Fos expression, physiological and nerve fiber responses, optogenetic and computational methods. RESULTS: Intermittent kHz stimulation for 30 min activates specific motor and, preferentially, sensory vagus neurons in the brainstem. At sufficiently high frequencies (>5 kHz) and at intensities within a specific range (7-10 times activation threshold, T, in rats; 15-25 × T in mice), C-afferents are activated, whereas larger, A- and B-fibers, are blocked. This was determined by measuring fiber-specific acute physiological responses to kHz stimulus trains, and by assessing fiber excitability around kHz stimulus trains through compound action potentials evoked by probing pulses. Aspects of selective activation of C-afferents are explained in computational models of nerve fibers by how fiber size and myelin shape the response of sodium channels to kHz-frequency stimuli. CONCLUSION: kHz stimulation is a neuromodulation strategy to robustly and selectively activate vagal C-afferents implicated in physiological homeostasis and disease, over larger vagal fibers.

A Computational Model of Functionally-distinct Cervical Vagus Nerve Fibers.

Cervical vagus nerve stimulation (VNS) is a neuromodulation therapy used in the treatment of several chronic disorders. In order to maximize the therapeutic effectiveness of VNS, it has become increasingly important to deliver fiber-specific neurostimulation, so that undesired effects can be minimized. Assessing the activation of different vagal fiber types through electrical stimulation is therefore essential for developing fiber-selective VNS therapies. Towards this goal, we conducted in silico investigations using a generic model of functionally distinct nerve fibers and clinically relevant cuff electrodes using COMSOL. Our model is constrained by histological observations from rat cervical vagus nerves and its outputs are validated against averaged compound nerve action potentials (CNAPs) obtained from rat vagus nerve recordings. We propose this model as an effective tool to design fiber-specific stimulation protocols before testing them in experimental animals.

Highly sensitive and wide-detection range pressure sensor constructed on a hierarchical-structured conductive fabric as a human-machine interface.

With the booming development of flexible pressure sensors, the need for multifunctional and high-performance pressure sensor has become increasingly important. Although great progress has been made in the novel structure and sensing mechanism of the pressure sensor, the trade-off between the sensitivity and the wide-detection range has prevented its development, further restricting its application in wearable human-machine interfaces (WHMIs). Herein, a novel pressure sensor based on the hierarchical conductive fabric was fabricated and purposed as a WHMI. Poly(3,4-ethylenedioxythiophene) nanowires (PEDOT NWs) and cellulose nanofibers (CNF) were stacked on a conductive poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS) fabric to form a special spatial multi-level hierarchical structure inside the fabric, which is a breakthrough for the improvement of the sensor's performance and makes the fabrication process of in situ polymerization suitable for large-scale production. The multi-level hierarchical structures endowed the pressure sensor with characteristics of high sensitivity (15.78 kPa-1), a wide-detection range from 30 Pa to 700 kPa, and outstanding stability toward compression and bending deformation. Benefiting from its excellent performance, a human-machine interface based on arrayed pressure sensors and signal processing system can control the illumination of the LED array and effectively capture finger motion to control the eight-direction movement of an unmanned aerial vehicle (UAV). This improved performance of the pressure sensor based on the hierarchical conductive fabric made it a widespread application in intelligent fabric, electronic skin, human-machine interfaces, and robotics.

Facile Fabrication of a Self-Healing Temperature-Sensitive Sensor Based on Ionogels and Its Application in Detection Human Breath.

The biocompatible strechable ionogels were prepared by a facile solution-processed method. The ionogels showed outstanding stretchable and self-healing properties. The electrical property could revert to its original state after 4 s. The repaired ionogels could still bear stretching about 150%. Moreover, the ionogels exhibited high sensitivity and wide-detection range to temperature. The temperature-sensitive sensor could detect the human breath frequency and intensity, showing potential application in detecting disease.

Effects of precompression time and strength on the physical characteristics of quasi-stapled porcine small intestinal tissue.

Precompression is vital when performing gastrointestinal anastomosis with staplers. However, research on the internal changes in intestinal tissue under stapling is lacking, and the effects of precompression have not been clarified. In this study, a stapler was modified, and the multifrequency bioimpedance of porcine small intestinal tissue was measured from before clamping the tissue with the stapler until the release of the tissue after precompression without firing. The Cole Y model was fitted to the bioimpedance, and the changes in the tissue were analyzed using the model parameters: G0, extracellular fluid conductance, and Δ G, intracellular fluid conductance. The results show that the changes of G0 and Δ G could be divided into four stages: rapid decrease, slow decrease, intense resilience, and slow recovery. During slow decrease stage, there was a greater decrease of G0 and Δ G (1.02E-05 ± 1.12E-05 S and 1.73E-05 ± 2.12E-05 S in precompression time's increase, 1.68E-05 ± 8.74E-06 S and 1.20E-05 ± 1.09E-05 S in precompression strength's increase). On the contrary, during intense resilience stage, there was a less increase of G0 and Δ G (0.88E-05 ± 4.86E-05 S and 9.15E-05 ± 9.37E-05 S in precompression time's increase, 2.72E-05 ± 3.53E-05 S and 1.02E-04 ± 8.54E-05 S in precompression strength's increase). In conclusion, the effects of precompression factors on tissue have been preliminary revealed: the tissue under precompression becomes thinner and less resilient. To improve the precompression effects and reduce any excessive pressure exerted on the staples by tissue resilience, the precompression time and strength should be increased appropriately.