Implant- and anesthesia-related factors affecting threshold intensities for vagus nerve stimulation

Abstract

Vagus nerve stimulation (VNS) is used as therapy in epilepsy and depression and is tested as a potential treatment for several chronic disorders. Typically, VNS is delivered at increasing stimulus intensity until a response is observed (threshold intensity). Factors that affect threshold intensities for engagement of different fiber types and concomitant physiological responses have not been studied. We determined neural and physiological responses to increasing stimulus intensities of VNS in anesthetized and awake animals, and examined the effect of implant- and anesthesia-related factors on threshold intensities in a rodent model of VNS. In acute and long-term cervical vagus nerve implants (53 and 14 rats, respectively) VNS was delivered under isoflurane, ketamine-xylazine, or awake at different intensities. Stimulus-evoked compound action potentials (eCAPs) were recorded, elicited physiological responses were registered, including changes heart rate (HR), breathing, and blood pressure (BP), and threshold intensities were determined. The intensity that elicits eCAPs (“neural threshold”) is significantly lower than what elicits a physiological response (“physiological threshold”, PT) (25 μA ±1.8 vs. 70 μA ±5.2, respectively; Mean ±SEM). Changes in BP occur at the lowest stimulus intensities (80 μA ±7), followed by changes in HR (105 μA ±8.4) and finally in breathing (310 μA ±32.5). PT is lower with than without electrode insulation (60 μA ±12, vs. 700 μA ±123). PT and electrode impedance are correlated in long-term (r=0.47; p<0.001) but not in acute implants (r=-0.34; p NS); both PT and impedance increase with implant age (Pearson correlation r=0.44; p<0.001 and r=0.64; p<0.001, respectively). PT is lowest when animals are awake (210 μA ±33; Mean ±SEM), followed by ketamine-xylazine (630 μA ±154), and isoflurane (1075 μA ±131). The sequence of physiological responses with increasing VNS intensity is similar in both anesthetized and awake states. Implant age, electrical impedance and the type of anesthesia affect VNS threshold and should be accounted for when determining stimulation dose.

Ultrasound Neuromodulation of the Spleen Has Time-Dependent Anti-Inflammatory Effect in a Pneumonia Model

“…Once the rats were under anesthesia, they were placed in a supine position, and hairs were removed using clippers and depilatory cream. The neck area was then cleaned using an aseptic technique, as described before ( 49 ). 1-2 cm horizontal skin incision was given on the neck, and salivary glands were separated.…”

A novel ex-vivo isolated rabbit heart preparation to explore the cardiac effects of cervical and cardiac vagus nerve stimulation

“…Therefore, vagus nerve stimulation (VNS) has been considered to be a promising therapeutic approach to treat diverse pathological conditions, such as epilepsy 5-8 , depression 9 , and cardiac diseases 10-14 by restoring the vagal tone to a physiological level.In cardiac medicine, VNS has proven to promote cardioprotective and anti-fibrillatory effects, thus providing a promising therapeutic approach for non-pharmacological treatment of various cardiac pathological conditions, such as ventricular arrhythmias 15 , atrial fibrillation 13 and heart failure 16,17 . However, the fact that VNS is mostly applied to the cervical level due to surgical ease of access and the possibility to target various organ-related fibers, it is often accompanied by difficultly controllable systemic off-target effects [18][19][20] .Although numerous studies have explored diverse effects of VNS on HR and hemodynamic function, invivo 11,[21][22][23][24] and in-situ 10,[25][26][27] , including anti-antiarrhythmic 15 and cardioprotective effects 28 , or alleviation of hypertension 29 , the outcomes are diverse, and the impact of VNS on the cardiac activity is still not fully understood. One main hindrance to better understand the cardiac effects of VNS is the presence of autonomic reflexes in-vivo, anesthetic and analgesic effects, and inter-individual variations.Addressing this problem, the purpose of this study was to establish a novel model of vagally innervated and fully isolated rabbit heart in order to study the cardiac effects of ex-vivo VNS under well-controllable und reproducible experimental conditions.…”

“…Although numerous studies have explored diverse effects of VNS on HR and hemodynamic function, invivo 11,[21][22][23][24] and in-situ 10,[25][26][27] , including anti-antiarrhythmic 15 and cardioprotective effects 28 , or alleviation of hypertension 29 , the outcomes are diverse, and the impact of VNS on the cardiac activity is still not fully understood. One main hindrance to better understand the cardiac effects of VNS is the presence of autonomic reflexes in-vivo, anesthetic and analgesic effects, and inter-individual variations.…”

Intermittent KHz-frequency electrical stimulation selectively engages small unmyelinated vagal afferents

“…Isoflurane anesthesia is commonly used in vagus and carotid sinus nerve stimulation studies 90 . Even though is does not alter direct electrical activation of vagus fibers 83 , it has been recently shown that it significantly increases physiological threshold intensities of VNS 57 . Anesthesia used in our study likely impacts synaptic transmission at the vagal ganglia and blunts baroreflex mediated cardiac responses, even though baroreceptor activation-induced heart rate changes are still observed at high isoflurane concentrations 91 .…”

“…This is possibly related to the proximity between the targeted fiber and the stimulating electrode and is critically dependent on the robustness of the neural interface. As a result, waveform manipulations may be less attractive in therapies relying on long-term implants, which generally show longitudinal changes in stimulation effectiveness 56,57 , or when scaling to larger diameter, more complex nerves in large animal models or humans, where there is more anatomical variability in the nerve-electrode interface 58 .…”