Selective stimulation of the ferret abdominal vagus nerve with multi-contact nerve cuff electrodes

Abstract

Dysfunction and diseases of the gastrointestinal (GI) tract are a major driver of medical care. The vagus nerve innervates and controls multiple organs of the GI tract and vagus nerve stimulation (VNS) could provide a means for affecting GI function and treating disease. However, the vagus nerve also innervates many other organs throughout the body, and off-target effects of VNS could cause major side effects such as changes in blood pressure. In this study, we aimed to achieve selective stimulation of populations of vagal afferents using a multi-contact cuff electrode wrapped around the abdominal trunks of the vagus nerve. Four-contact nerve cuff electrodes were implanted around the dorsal (N = 3) or ventral (N = 3) abdominal vagus nerve in six ferrets, and the response to stimulation was measured via a 32-channel microelectrode array (MEA) inserted into the left or right nodose ganglion. Selectivity was characterized by the ability to evoke responses in MEA channels through one bipolar pair of cuff contacts but not through the other bipolar pair. We demonstrated that it was possible to selectively activate subpopulations of vagal neurons using abdominal VNS. Additionally, we quantified the conduction velocity of evoked responses to determine what types of nerve fibers (i.e., Aδ vs. C) responded to stimulation. We also quantified the spatial organization of evoked responses in the nodose MEA to determine if there is somatotopic organization of the neurons in that ganglion. Finally, we demonstrated in a separate set of three ferrets that stimulation of the abdominal vagus via a four-contact cuff could selectively alter gastric myoelectric activity, suggesting that abdominal VNS can potentially be used to control GI function.

Spatially selective stimulation of the pig vagus nerve to modulate target effect versus side effect

“…Recent studies of VNS suggest that smaller, multi-contact electrodes may provide better selectivity for isolating desired therapeutic effects from off-target side effects (Fitchett et al, 2021; Ordelman et al, 2013; Shulgach et al, 2021). Specifically, the studies demonstrated that the magnitude of heart rate changes may be altered by changing the electrode location around the circumference of the VN.…”

Physiological changes associated with copper sulfate-induced nausea and retching in felines

“…As in our prior experiments ( Patel et al, 2018 ; Bielanin et al, 2020 ; Miller et al, 2020 ), animals were gradually acclimated over at least 5 weeks for 1-h of confinement in a nylon restraint bag attached to a recording platform using Velcro straps. Subsequently, an aseptic recovery surgery was performed in a dedicated operating suite as described below to attach two-contact platinum-iridium 90/10 electrodes in a silicone patch (Micro-leads Inc, Somerville, MA, United States), similar to those used in prior studies ( Nanivadekar et al, 2019 ; Shulgach et al, 2021 ), to the proximal duodenum and gastric antrum, on the ventral surface ( Figure 1 ). In addition, custom-fabricated electrodes consisting of flexible insulated wire (Cooner Wire, Chatsworth, CA United States) embedded in medical grade silicon (Bentec Medical, Woodland, CA United States) were attached to the diaphragm and abdominal muscles ( Figure 1 ).…”

“…The acute action of this agent allowed us to monitor a variety of physiologic parameters prior to emesis during a controlled recording session. Before and following CuSO 4 treatment we recorded heart rate, respiration rate, and gastric and duodenal myoelectric responses using methodology developed through our work in ferrets ( Nanivadekar et al, 2019 ; Shulgach et al, 2021 ). The dose of CuSO 4 was additionally varied between animals so we could determine whether increasing the dose altered physiologic responses prior to emesis.…”

Physiological Changes Associated with Copper Sulfate-Induced Emesis in Felines

“…As in our prior experiments (Patel et al, 2018; Bielanin et al, 2020; Miller et al, 2020), animals were gradually acclimated over at least 5 weeks for 1-hour of confinement in a nylon restraint bag attached to a recording platform using Velcro straps. Subsequently, an aseptic recovery surgery was performed in a dedicated operating suite as described below to attach two-contact platinum-iridium 90/10 electrodes in a silicone patch (Micro-leads Inc., Somerville, MA, USA), similar to those used in prior studies (Nanivadekar et al, 2019; Shulgach et al, 2021), to the proximal duodenum and gastric antrum, on the ventral surface ( Figure 1 ). In addition, custom-fabricated electrodes consisting of flexible insulated wire (Cooner Wire, Chatsworth, CA USA) embedded in medical grade silicon (Bentec Medical, Woodland, CA USA) were attached to the diaphragm and abdominal muscles ( Figure 1 ).…”