Modulation of heart rate by temporally patterned vagus nerve stimulation in the anesthetized dog.

Despite current knowledge of the myriad physiological effects of vagus nerve stimulation (VNS) in various mammalian species (including humans), the impact of varying stimulation parameters on nerve recruitment and physiological responses is not well understood. We investigated nerve recruitment, cardiovascular responses, and skeletal muscle responses to different temporal patterns of VNS across 39 combinations of stimulation amplitude, frequency, and number of pulses per burst. Anesthetized dogs were implanted with stimulating and recording cuff electrodes around the cervical vagus nerve, whereas laryngeal electromyogram (EMG) and heart rate were recorded. In seven of eight dogs, VNS-evoked bradycardia (defined as ≥10% decrease in heart rate) was achieved by applying stimuli at amplitudes equal to or greater than the threshold for activating slow B-fibers. Temporally patterned VNS (minimum 5 pulses per burst) was sufficient to elicit bradycardia while reducing the concomitant activation of laryngeal muscles by more than 50%. Temporal patterns of VNS can be used to modulate heart rate while minimizing laryngeal motor fiber activation, and this is a novel approach to reduce the side effects produced by VNS.

Selection of muscle and nerve-cuff electrodes for neuroprostheses using customizable musculoskeletal model.

Neuroprosthetic systems based on functional electrical stimulation aim to restore motor function to individuals with paralysis following spinal cord injury. Identifying the optimal electrode set for the neuroprosthesis is complicated because it depends on the characteristics of the individual (such as injury level), the force capacities of the muscles, the movements the system aims to restore, and the hardware limitations (number and type of electrodes available). An electrode-selection method has been developed that uses a customized musculoskeletal model. Candidate electrode sets are created based on desired functional outcomes and the hard ware limitations of the proposed system. Inverse-dynamic simulations are performed to determine the proportion of target movements that can be accomplished with each set; the set that allows the most movements to be performed is chosen as the optimal set. The technique is demonstrated here for a system recently developed by our research group to restore whole-arm movement to individuals with high-level tetraplegia. The optimal set included selective nerve-cuff electrodes for the radial and musculocutaneous nerves; single-channel cuffs for the axillary, suprascapular, upper subscapular, and long-thoracic nerves; and muscle-based electrodes for the remaining channels. The importance of functional goals, hardware limitations, muscle and nerve anatomy, and surgical feasibility are highlighted.

High-resolution measurement of electrically-evoked vagus nerve activity in the anesthetized dog.

OBJECTIVE: Not fully understanding the type of axons activated during vagus nerve stimulation (VNS) is one of several factors that limit the clinical efficacy of VNS therapies. The main goal of this study was to characterize the electrical recruitment of both myelinated and unmyelinated fibers within the cervical vagus nerve. APPROACH: In anesthetized dogs, recording nerve cuff electrodes were implanted on the vagus nerve following surgical excision of the epineurium. Both the vagal electroneurogram (ENG) and laryngeal muscle activity were recorded in response to stimulation of the right vagus nerve. MAIN RESULTS: Desheathing the nerve significantly increased the signal-to-noise ratio of the ENG by 1.2 to 9.9 dB, depending on the nerve fiber type. Repeated VNS following nerve transection or neuromuscular block (1) enabled the characterization of A-fibers, two sub-types of B-fibers, and unmyelinated C-fibers, (2) confirmed the absence of stimulation-evoked reflex compound nerve action potentials in both the ipsilateral and contralateral vagus nerves, and (3) provided evidence of stimulus spillover into muscle tissue surrounding the stimulating electrode. SIGNIFICANCE: Given the anatomical similarities between the canine and human vagus nerves, the results of this study provide a template for better understanding the nerve fiber recruitment patterns associated with VNS therapies.

Excitation properties of the right cervical vagus nerve in adult dogs.

Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and depression, and it is currently under investigation for applications in Alzheimer's disease, anxiety, heart failure, and obesity. However, the mechanism(s) by which VNS has its effects are not clear, and the stimulation parameters for obtaining therapeutic outcomes appear highly variable. The purpose of this study was to quantify the excitation properties of the right cervical vagus nerve in adult dogs anesthetized with propofol and fentanyl. Input-output curves of the right cervical vagus nerve compound action potential and laryngeal muscle electromyogram were measured in response to VNS across a range of stimulation parameters: amplitudes of 0.02-50mA, pulsewidths of 10, 50, 100, 200, 300, 500, and 1,000µs, frequencies of 1-2Hz, and train lengths of 20 pulses with 3 different electrode configurations: monopolar cathode, proximal anode/distal cathode, and proximal cathode/distal anode. Electrode configuration and stimulation waveform (monophasic vs. asymmetric charge-balanced biphasic) did not affect the threshold or recruitment of the vagal nerve fibers that were activated. The rheobase currents of A- and B-fibers were 0.4mA and 0.7mA, respectively, and the chronaxie of both components was 180µs. Pulsewidth had little effect on the normalized threshold difference between activation of A- and B-fibers. The results provide insight into the complement of nerve fibers activated by VNS and guidance to clinicians for the selection of optimal stimulation parameters.

Selective control of physiological responses by temporally-patterned electrical stimulation of the canine vagus nerve.

Vagus nerve stimulation (VNS) is effective for treating epilepsy and depression, and has emerging indications for anxiety and heart failure. However, stimulation-evoked side effects remain a challenge for long-term compliance. We investigated the feasibility of reducing VNS side effects by using a temporally-modified stimulation pattern. In 4 anesthetized canines, we measured changes in both the heart rate and evoked laryngeal muscle activity. Compared to baseline, we found that a 5% duty cycle (measured by the number of pulses per second of stimulation) could still evoke a 21% reduction in heart rate; whereas compared to continuous stimulation (3 mA, 300 µs pulsewidth, 20 Hz) the same 5% duty cycle reduced the evoked laryngeal muscle activity by 90%. The results of this study indicate that temporally-patterned stimulation may provide an effective tool for optimizing VNS therapy.

A musculoskeletal model of the upper extremity for use in the development of neuroprosthetic systems.

Upper extremity neuroprostheses use functional electrical stimulation (FES) to restore arm motor function to individuals with cervical level spinal cord injury. For the design and testing of these systems, a biomechanical model of the shoulder and elbow has been developed, to be used as a substitute for the human arm. It can be used to design and evaluate specific implementations of FES systems, as well as FES controllers. The model can be customized to simulate a variety of pathological conditions. For example, by adjusting the maximum force the muscles can produce, the model can be used to simulate an individual with tetraplegia and to explore the effects of FES of different muscle sets. The model comprises six bones, five joints, nine degrees of freedom, and 29 shoulder and arm muscles. It was developed using commercial, graphics-based modeling and simulation packages that are easily accessible to other researchers and can be readily interfaced to other analysis packages. It can be used for both forward-dynamic (inputs: muscle activation and external load; outputs: motions) and inverse-dynamic (inputs: motions and external load; outputs: muscle activation) simulations. Our model was verified by comparing the model calculated muscle activations to electromyographic signals recorded from shoulder and arm muscles of five subjects. As an example of its application to neuroprosthesis design, the model was used to demonstrate the importance of rotator cuff muscle stimulation when aiming to restore humeral elevation. It is concluded that this model is a useful tool in the development and implementation of upper extremity neuroprosthetic systems.