Excitation properties of the right cervical vagus nerve in adult dogs
Research highlights
►Electrical stimulation of the right vagus nerve elicits bidirectional activity of A, B and C fibers. ►Low stimulation threshold responses (A-fibers) corresponded to recurrent laryngeal nerve fibers. ►Stimulation and electrode parameters have limited effect on the dynamic range of fiber activation.
Introduction
The vagus nerve represents a large portion of the peripheral autonomic nervous system, and many chronic diseases are thought to involve an imbalance between the parasympathetic and sympathetic components (Tracey, 2002). Vagus nerve stimulation (VNS) was approved by the Food and Drug Administration for the treatment of epilepsy (1997) and depression (2005), and is currently under investigation for applications in Alzheimer's disease, anxiety, heart failure, inflammatory disease and obesity (Groves and Brown, 2005, Li et al., 2004, Milby et al., 2008, Schwartz et al., 2008, Tracey, 2002, Vanoli et al., 1991). 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, which represents a less common but effective site for therapeutic electrical stimulation (Navas et al., 2010, Schwartz et al., 2008, Spuck et al., 2008). Specifically, we measured the relationship between the amplitude and pulsewidth of stimulation using different electrode configurations and the activation of different diameter nerve fibers.
The vagus nerve originates in the medulla and innervates organs of the neck, thorax, and abdomen. The cervical vagus nerve of an adult dog contains approximately 20,000 myelinated nerve fibers (Satchell et al., 1982), and an even greater number of unmyelinated nerve fibers. Studies in rabbits and cats report unmyelinated nerve fiber population estimates of 65–85% (Evans and Murray, 1954, Mei et al., 1980). Afferents from the esophagus, gastrointestinal tract, heart, and lungs outnumber somatic efferents of the voluntary muscles of the neck and parasympathetic efferents of the visceral organs by a ratio of 4:1 (Brodal, 1981, Foley and DuBois, 1937, Paintal, 1973, Rutecki, 1990). Cardiac efferents in the left vagus nerve are associated with the atrioventricular node, regulating cardiac contractility, while cardiac efferents in the right vagus nerve are associated with the sinoatrial node, regulating heart rate (Saper et al., 1990, Schachter and Saper, 1998). Mammalian vagal nerve fibers are divided into 3 populations: A, B, and C, whose characteristics are summarized in Table 1 (Berthold, 1978, Erlanger and Gasser, 1930, Groves and Brown, 2005, Woodbury and Woodbury, 1990).
The relationship between stimulation parameters and activation of different populations of fibers within the cervical vagus nerve is not clear, and the stimulation parameters appropriate to maximize intended therapeutic effects and mitigate side effects have not been identified. Recommended stimulation parameters from previous preclinical studies to suppress or terminate seizures using VNS are wide ranging: 2–20 mA, 200 μs, 20–30 Hz, and 30 s on/variable off (Zabara, 1992); 0.2–0.5 mA/mm2 of nerve cross-section, 500–1,000 μs, 10–20 Hz, and 30 s on/variable off (Woodbury and Woodbury, 1990). Similar variability is also observed from previous clinical studies: 0.25–3.5 mA, 130–500 μs, 20–30 Hz, and variable duty trains (Koo et al., 2001); ≤ 3.5 mA, 500 μs, 20–50 Hz, and 30–90 s on/5–10 min off (Ben-Menachem et al., 1994, George et al., 1994, Handforth et al., 1998, Penry and Dean, 1990, Ramsay et al., 1994, Uthman et al., 1993).
Experiments were conducted in adult dogs to record the neural and laryngeal muscle responses to graded stimulation of the right cervical vagus nerve using different electrode configurations. Since conduction velocity (θ) is proportional to fiber diameter (d) for myelinated fibers, θ/d ≈ 6 m/s/μm (Hursh, 1939), and proportional to the square root of fiber diameter for unmyelinated fibers, θ(m/s) ≈ [d(μm)]1/2 (Pumphrey and Young, 1938), the latency of the components of the compound action potential (CAP) are correlated with fiber diameter (Braund et al., 1988). This allowed us to differentiate the contributions of A-, B-, and C-fibers to the overall CAP, and generate input–output curves of the proportion of each evoked component as a function of stimulation intensity. The specific aims of this study were to characterize the relationships between stimulation intensity, electrode configuration, and waveform (monophasic vs. asymmetric charge-balanced biphasic) on the population of vagal nerve fibers that were activated, to measure the strength–duration properties of the CAP components, and to determine the effect of pulsewidth on the normalized threshold difference between activation of A- and B-fibers.
Section snippets
Preparation and instrumentation
This study was conducted on 7 female and 2 male adult dogs weighing 18–21 kg. All procedures were reviewed and approved by the Institutional Animal Care and Use Committee at Duke University. Animals were fasted (12–24 h) and a fentanyl transdermal patch (50 μg/h for dogs < 20 kg and 75 μg/h for dogs ≥ 20 kg) was applied to the back of the neck prior to surgery. At the beginning of the experiment, animals were sedated with thiopental sodium (20 mg/kg, i.v.), and anesthesia was induced by inhalation of
Neural and laryngeal muscle responses evoked by VNS
The evoked neural and laryngeal muscle responses from one experiment are shown in Fig. 2. The latencies of A- and B-components in Fig. 2 are approximately 2–4 ms and 5–9 ms, respectively. At a distance of 13 cm between the distal stimulating electrode and the recording electrode (Fig. 1), these latencies correspond to conduction velocities of 32–65 m/s and 14–26 m/s, respectively, both within the expected ranges (Table 1). Because of neuromuscular transmission and the 20–30 cm of additional
Discussion
The objective of this study was to quantify the excitation properties of the right cervical vagus nerve, and thereby provide information that might guide selection of stimulation parameters for therapeutic applications of VNS. The results indicate that the contributions of A-, B-, and C-fibers to the rCAP can be distinguished, that neither electrode configuration (MonoC vs. PADC vs. PCDA) nor stimulation waveform (monophasic vs. asymmetric charge-balanced biphasic) affected recruitment of the
Conclusion
Although the number of patients implanted with a VNS device has more than doubled to 50,000 over the last 5 years, the mechanism(s) by which VNS has its effects are not clear and the stimulation parameters for obtaining therapeutic outcome appear highly variable (Borusiak et al., 2009, Groves and Brown, 2005). Our results provide information to estimate the population of vagal nerve fibers that are activated at different stimulation intensities and with different electrode configurations and the
Acknowledgments
The authors would like to thank Ellen Dixon-Tulloch and Gilda Mills for their assistance with animal preparation and monitoring during the experiments. This work was supported by a grant from Boston Scientific Corporation.
References (45)
- et al.
Vagus nerve stimulation for epilepsy activates the vocal folds maximally at therapeutic levels
Epilepsy Res.
(2010) - et al.
Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects
Neurosci. Biobehav. Rev.
(2005) - et al.
Excitability characteristics of the A- and C-fibers in a peripheral nerve
Exp. Neurol.
(1976) - et al.
Vagus nerve stimulation for epilepsy and depression
Neurotherapeutics
(2008) - et al.
Treatment of refractory epilepsy in adult patients with right-sided vagus nerve stimulation
Epilepsy Res.
(2010) - et al.
Right-sided vagus nerve stimulation in humans: an effective therapy?
Epilepsy Res.
(2008) - et al.
Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. First International Vagus Nerve Stimulation Study Group
Epilepsia
(1994) Morphology of Normal Peripheral Axons
- et al.
Late-onset cardiac arrhythmia associated with vagus nerve stimulation
J. Neurol.
(2009) - et al.
Morphologic and morphometric studies of the vagus and recurrent laryngeal nerves in clinically normal adult dogs
Am. J. Vet. Res.
(1988)
Neurological Anatomy in Relation to Clinical Medicine
The action potential in fibers of slow conduction in spinal roots and somatic nerves
Am. J. Physiol.
Histological and functional studies on the fibre composition of the vagus nerve of the rabbit
J. Anat.
Quantitative studies of the vagus nerve in the cat—I. The ratio of sensory to motor fibers
J. Comp. Neurol.
Vagus nerve stimulation for treatment of partial seizures: 3. Long-term follow-up on first 67 patients exiting a controlled study. First International Vagus Nerve Stimulation Study Group
Epilepsia
Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial
Neurology
Effect of anodal blockade of myelinated fibers on vagal C-fiber afferents
Am. J. Physiol.
Conduction velocity and diameter of nerve fibers
Am. J. Physiol.
Heart rate responses to selective stimulation of cardiac vagal C fibres in anaesthetized cats, rats and rabbits
J. Physiol.
Human vagus nerve electrophysiology: a guide to vagus nerve stimulation parameters
J. Clin. Neurophysiol.
Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression in rats
Epilepsia
Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats
Circulation
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