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

Paul B Yoo, Haoran Liu, Juan G Hincapie, Stephen B Ruble, Jason J Hamann, Warren M Grill, Paul B Yoo, Haoran Liu, Juan G Hincapie, Stephen B Ruble, Jason J Hamann, Warren M Grill

Abstract

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.

Keywords: Bradycardia; dog; heart failure; neuromodulation therapy; temporal patterned stimulation; vagus nerve stimulation.

© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Figures

Figure 1
Figure 1
Temporally patterned vagus nerve stimulation (IPI = interpulse interval = frequency−1, IBI = interburst interval).
Figure 2
Figure 2
Sample data of electrically evoked signals from (A) the ipsilateral vagus nerve and (B) the laryngeal muscle. The recorded compound nerve action potential signal shows orderly recruitment of large diameter A fibers (1 –1.5 mA), B fibers (2 mA), and slow B‐fibers (5 mA, labeled as Bs). According to our previous study, this corresponded to conduction velocities of 38.8 ± 4.8 m/sec (A‐Fiber), 18.0 ± 4.7 m/sec (fast B‐fiber), and 10.5 ± 1.9 m/sec (slow B‐fiber). The laryngeal electromyogram shows the corresponding threshold activation of motor fibers at approximately 1.1 mA (arrow), and maximum muscle fiber recruitment at 1.5 mA.
Figure 3
Figure 3
Continuous electrical stimulation of the right vagus nerve in anesthetized dogs (duration = 20‐sec, frequency = 20 Hz). (A) Response curve obtained from a single experiment, where the normalized heart rate was plotted against the stimulation amplitude. The bradycardia threshold (BCT) was 2 mA. (B) Electrical stimulation at 4 mA resulted in significant bradycardia (electrocardiogram, EKG), and correspondingly evoked neural (ENG) and muscle (laryngeal EMG) responses. (C) Zoomed image of the first electrical pulse shows the short‐latency ENG (1.8 msec) and longer‐latency EMG (9.5 msec) signals, which were repeated throughout the 20 sec of stimulation. [abscissa units: |EKG| ≤ 2.5 V, |ENG| ≤7.5 mV, and |Laryngeal EMG| ≤7.5 mV].
Figure 4
Figure 4
Activation thresholds of nerves fibers in the vagus nerve (n = 8 dogs) and bradycardia (BC) threshold. The bradycardia threshold coincided with the slow‐B fiber threshold. This relationship suggests that VNS‐evoked bradycardia is a result of the activation of this group of small, myelinated B‐fibers (*P ≤ 0.001).
Figure 5
Figure 5
Characteristic cardiac effects of VNS (50 Hz, 20 pulses per burst, 5 mA – above bradycardia threshold). Stimulation pattern, electrocardiogram (EKG), and arterial blood pressure (ABP).
Figure 6
Figure 6
Continuous electrical stimulation of the (A) intact and (C) distal stump of the transected cervical vagus nerve both resulted in acute asystole (above BCT, 20 Hz). During stimulation‐evoked asystole, ventricular escape beats were commonly observed, as shown in panel C. In contrast, electrical stimulation of the (B) proximal stump of the transected cervical vagus nerve did not elicit any changes in cardiac function. [units per division: time (4 sec), ECG (1.5 V), left ventricular pressure (62.5 mmHg), arterial blood pressure (25 mmHg)].

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