Stimulation parameters for directional vagus nerve stimulation

Abstract

Background: Autonomic nerve stimulation is used as a treatment for a growing number of diseases. We have previously demonstrated that application of efferent vagus nerve stimulation (eVNS) has promising glucose lowering effects in a rat model of type 2 diabetes. This paradigm combines high frequency pulsatile stimulation to block nerve activation in the afferent direction with low frequency stimulation to activate the efferent nerve section. In this study we explored the effects of the parameters for nerve blocking on the ability to inhibit nerve activation in the afferent direction. The overarching aim is to establish a blocking stimulation strategy that could be applied using commercially available implantable pulse generators used in the clinic.

Methods: Male rats (n = 20) had the anterior abdominal vagus nerve implanted with a multi-electrode cuff. Evoked compound action potentials (ECAP) were recorded at the proximal end of the electrode cuff. The efficacy of high frequency stimulation to block the afferent ECAP was assessed by changes in the threshold and saturation level of the response. Blocking frequency and duty cycle of the blocking pulses were varied while maintaining a constant 4 mA current amplitude.

Results: During application of blocking at lower frequencies (≤ 4 kHz), the ECAP threshold increased (ANOVA, p < 0.001) and saturation level decreased (p < 0.001). Application of higher duty cycles (> 70%) led to an increase in evoked neural response threshold (p < 0.001) and a decrease in saturation level (p < 0.001). During the application of a constant pulse width and frequency (1 or 1.6 kHz, > 70% duty cycle), the charge delivered per pulse had a significant influence on the magnitude of the block (ANOVA, p = 0.003), and was focal (< 2 mm range).

Conclusions: This study has determined the range of frequencies, duty cycles and currents of high frequency stimulation that generate an efficacious, focal axonal block of a predominantly C-fiber tract. These findings could have potential application for the treatment of type 2 diabetes.

Keywords: Bioelectric medicine; Medical devices; Metabolic disease; Nerve blocking; Peripheral nerve stimulation.

Fig. 1

Electrophysiology methods. A Diagram defining the stimulation pulse timing parameters used for analysis. B Example of evoked compound action potentials (ECAPs) in rat vagus nerve quantified at increasing activation current amplitude in the period 3–9 ms post-stimulus (shaded area). This ECAP was recorded on the rostral electrode pair during 10 kHz, 80% duty cycle and 4 mA current blocking stimuli applied to the middle electrode pair. C The resultant ECAP RMS response (generated from the shaded area in B) to stimulus current was fit with a sigmoidal curve to identify response saturation level and threshold. D ECAP responses (threshold and saturation) were compared at various blocking frequencies (1.6 – 26 kHz) and duty cycles (1 / frequency—18 μs) / 2, displayed as %)

Fig. 2

Effect of frequency and duty cycle on blocking efficacy. A Effect of blocking stimulation frequency on the ECAP response, showing threshold on top and saturation amplitude at the bottom. B Relative change with each blocking frequency vs. control ECAPs in the same experiment (mean ± std. error). The blocking effects were more evident at lower kilohertz frequencies. C Effect of blocking stimulus duty cycle on the ECAP response, where high duty cycles improved block. Threshold on top and saturation amplitude on the bottom. D Relative change with each duty cycle vs. control ECAPs in the same experiment. The blocking effects were more evident at higher (≥ 70%) duty cycles. Data in A and C show individual values (indicated by ‘x’), while data in B and D indicate mean ± SEM

Fig. 3

Signal extraction. Correlation of changes in ECAP threshold vs saturation amplitude, expressed as ratio to control (no-block) condition. Dots indicate data from individual recordings, while the line shows linear fit (r = -0.81, p < 0.0001)

Fig. 4

Estimation of ECAP block (change in threshold and saturation amplitude) with respect to various combinations of pulse timing parameters of the blocking stimuli. The color indicates magnitude of the change in ECAP, while the size of each circle indicates the number of animals aggregated for that parameter combination. The contour curves show a 3rd order polynomial fit as visual aid

Fig. 5

Comparison of the effect of charge per pulse on nerve block, by varying either current level or pulse width. Lines show linear fit for each stimulation mode and frequency

Fig. 6

Spatial extent of the nerve block. The location of activating and blocking stimuli were exchanged so that blocking was applied to the caudal electrode pair, activating stimuli to the middle pair and recording on the rostral pair to assess the focality of the nerve. Assessment of afferent and efferent vagus nerve stimulation (aVNS, eVNS) in 6-electrode array (electrode pairs were 3.4 mm apart: (A, A1) and 8-electrode array (electrode pairs were 2.22 mm apart: B, B1) design. Data in A1 (n = 3) and B1 (n = 2) show mean ± SEM