Selective Vagus Nerve Stimulation Research Articles

Afferent selective vagus nerve stimulation reduces TLR7 induced acute lung inflammation

Background: Vagus nerve stimulation (VNS) has recently been introduced as a nonpharmacological therapy for disease characterized by an exacerbated immune response, with clinical trials demonstrating its efficacy for autoimmunity and sepsis by reducing inflammatory proteins and improving disease scores. To date, much of these anti-inflammatory effects have been attributed to vagal efferent (motor) signaling in a mechanism referred to as the cholinergic anti-inflammatory pathway (CAIP). Recent studies from our lab, as well as others, have begun to highlight alternative neuro-immune regulation by the vagus nerve, independent from the CAIP. The scope of these neuro-immune interactions, including target tissues and cell types, however, is still unclear. Although the lung is densely innervated, it is unknown how VNS can reduce acute TLR7 agonist-induced lung inflammation. Hypothesis: We sought to determine whether VNS was effective at reducing acute lung inflammation induced by viral mimetic and TLR7/8 agonist Resiquimod (R848). Methods: The right cervical vagus nerves of C57BL/6 mice were stimulated electrically (5V, 5Hz) for 20 minutes. A 0.25mg/kg dose of R848 was instilled 10 minutes after beginning VNS. 1 hour post-R848 challenge, relevant tissues were prepared for qPCR, flow cytometry, or ELISA. Results: Stimulation of the right vagus nerve was able to significantly decrease R848-induced mRNA expression of pro-inflammatory cytokines TNFα and IFNβ, as well as chemokines CCL4 and CXCL1 within the lung. This decrease occurred independently of the cells responsible for the CAIP (CD4+ ChAT+ T-cells), indicating a novel neuro-immune mechanism with a new target organ. Flow cytometry revealed that alveolar macrophages and neutrophils were the primary immune cell populations responding to R848 and subsequently modified by VNS, with significant reductions in intracellular staining for TNFα. Epinephrine and norepinephrine were significantly elevated within the serum during the first 5 minutes of VNS, but fluid from bronchoalveolar lavage revealed significant increases of only epinephrine within the lung. Subsequently, removal of the adrenal glands, the primary source of epinephrine, eliminated the anti-inflammatory effect of VNS. Elevation of epinephrine suggests an immunomodulatory role for the β2AR, with further studies using a highly selective antagonist ICI 118 551 or β2AR KO mice eliminating VNS-induced protection. Finally, using optogenetics we were able to identify vagal afferent neurons as the fibers responsible for modulating immune cell activation within the lung. Conclusion: These studies highlight a novel neuro-immune mechanism within the lung capable of regulating viral mimetic-induced inflammation. Facilitated by vagal afferent neurons, we show that VNS elicits adrenal gland-derived epinephrine release that acts through the β2AR to reduce macrophage activation and neutrophil recruitment in the lung. Chan-Zuckerberg Initiative (2020-217656); Graduate Student Support Program (UC Davis: School of Veterinary Medicine); NIH T32 GM (GM099608, GM144303) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Fractal Microelectrodes for More Energy-Efficient Cervical Vagus Nerve Stimulation.

Vagus nerve stimulation (VNS) has the potential to treat various peripheral dysfunctions, but the traditional cuff electrodes for VNS are susceptible to off-target effects. Microelectrodes may enable highly selective VNS that can mitigate off-target effects, but they suffer from the increased impedance. Recent studies on microelectrodes with non-Euclidean geometries have reported higher energy efficiency in neural stimulation applications. These previous studies use electrodes with mm/cm-scale dimensions, mostly targeted for myelinated fibers. This study evaluates fractal microelectrodes for VNS in a rodent model (N = 3). A thin-film device with fractal and circle microelectrodes is fabricated to compare their neural stimulation performance on the same radial coordinate of the nerve. The results show that fractal microelectrodes can activate C-fibers with up to 52% less energy (p = 0.012) compared to circle microelectrodes. To the best of the knowledge, this work is the first to demonstrate a geometric advantage of fractal microelectrodes for VNS in vivo.

Organ- and function-specific anatomical organization of vagal fibers supports fascicular vagus nerve stimulation

Vagal fibers travel inside fascicles and form branches to innervate organs and regulate organ functions. Existing vagus nerve stimulation (VNS) therapies activate vagal fibers non-selectively, often resulting in reduced efficacy and side effects from non-targeted organs. The transverse and longitudinal arrangement of fibers inside the vagal trunk with respect to the functions they mediate and organs they innervate is unknown, however it is crucial for selective VNS. Using micro-computed tomography imaging, we tracked fascicular trajectories and found that, in swine, sensory and motor fascicles are spatially separated cephalad, close to the nodose ganglion, and merge caudad, towards the lower cervical and upper thoracic region; larynx-, heart- and lung-specific fascicles are separated caudad and progressively merge cephalad. Using quantified immunohistochemistry at single fiber level, we identified and characterized all vagal fibers and found that fibers of different morphological types are differentially distributed in fascicles: myelinated afferents and efferents occupy separate fascicles, myelinated and unmyelinated efferents also occupy separate fascicles, and small unmyelinated afferents are widely distributed within most fascicles. We developed a multi-contact cuff electrode to accommodate the fascicular structure of the vagal trunk and used it to deliver fascicle-selective cervical VNS in anesthetized and awake swine. Compound action potentials from distinct fiber types, and physiological responses from different organs, including laryngeal muscle, cough, breathing, and heart rate responses are elicited in a radially asymmetric manner, with consistent angular separations that agree with the documented fascicular organization. These results indicate that fibers in the trunk of the vagus nerve are anatomically organized according to functions they mediate and organs they innervate and can be asymmetrically activated by fascicular cervical VNS.

Fascicular Organisation and Neuroanatomy of the Porcine and Human Vagus Nerves: Allowing for Spatially Selective Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) often results in off‐target effects due to the unknown fascicular organisation of the cervical vagus nerve and thus nonspecific nature of stimulation. This currently limits its therapeutic efficacy in treating epilepsy and depression and restricts its extension to treating numerous other conditions, such as heart failure and lung injury, for which it could be a promising treatment. The purpose of this work was to determine the fascicular anatomical representation of the recurrent laryngeal, cardiac and pulmonary branches of the vagus nerve at the mid‐cervical level of VNS cuff placement in the vagus nerve in pigs using micro‐computed tomography (microCT) to trace anatomical connections to end‐organs with the intention of extension to humans.The left vagus nerves were dissected from mid‐cervical level to the branches of the lungs, heart and larynx in four domestic female 60‐70 kg pigs. Nerves were fixed, sectioned into 4 cm lengths with registration landmarks, soaked in Lugol’s solution (1% total iodine) for five days for sufficient contrast staining and microCT‐scanned (Nikon XT H 225, Nikon Metrology) with a molybdenum target and 7 µm voxel size, 35 kVp energy, 114 mA current, 4 W power, 0.25 fps in 4 s exposure time, and 3176 projections. Subsequently, scans were reconstructed in CT Pro 3D (Nikon Metrology) and analysed in ImageJ. Fascicles of the three target organs/fascicle groups were segmented and traced with Neurolucida 360 (MBF Bioscience) from the point the organ‐specific branch enters the vagus nerve to mid‐cervical level (20‐25 cm total length per nerve).The three identified fascicular groups remained discrete at the cervical level (26%, 23% and 4% of total vagus nerve area for pulmonary, recurrent laryngeal and cardiac fascicle groups, respectively, with significant separation of centres of mass (P<0.05)). These three distinct regions contained overlap only between a small number of pulmonary and recurrent laryngeal fascicles (<11%). The cardiac fascicles remained separate. This confirms organotopic organisation of the cervical vagus nerve according to organ/function for cardiac, pulmonary and recurrent laryngeal fascicles. Work is in progress to delineate similar fascicular organisation in excised cadaveric human vagus nerves. Knowledge of the fascicular organisation of the vagus nerve will enable accurate spatially selective VNS which may allow for avoidance of off‐target effects and so improve its therapeutic efficacy.

Selective Neuromodulation of the Vagus Nerve.

Vagus nerve stimulation (VNS) is an effective technique for the treatment of refractory epilepsy and shows potential for the treatment of a range of other serious conditions. However, until now stimulation has generally been supramaximal and non-selective, resulting in a range of side effects. Selective VNS (sVNS) aims to mitigate this by targeting specific fiber types within the nerve to produce functionally specific effects. In recent years, several key paradigms of sVNS have been developed—spatially selective, fiber-selective, anodal block, neural titration, and kilohertz electrical stimulation block—as well as various stimulation pulse parameters and electrode array geometries. sVNS can significantly reduce the severity of side effects, and in some cases increase efficacy of the treatment. While most studies have focused on fiber-selective sVNS, spatially selective sVNS has demonstrated comparable mitigation of side-effects. It has the potential to achieve greater specificity and provide crucial information about vagal nerve physiology. Anodal block achieves strong side-effect mitigation too, but is much less specific than fiber- and spatially selective paradigms. The major hurdle to achieving better selectivity of VNS is a limited knowledge of functional anatomical organization of vagus nerve. It is also crucial to optimize electrode array geometry and pulse shape, as well as expand the applications of sVNS beyond the current focus on cardiovascular disease.

Selective Vagus Nerve Stimulation as a Therapeutic Approach for the Treatment of ARDS: A Rationale for Neuro-Immunomodulation in COVID-19 Disease.

Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury. It is induced by sepsis, aspiration, and pneumonia, including that caused by SARS coronavirus and human influenza viruses. The main pathophysiological mechanism of ARDS is a systemic inflammatory response. Vagus nerve stimulation (VNS) can limit cytokine production in the spleen and thereby dampen any systemic inflammation and inflammation-induced tissue damage in the lungs and other organs. However, the effects of increased parasympathetic outflow to the lungs when non-selective VNS is applied may result in bronchoconstriction, increased mucus secretion and enhance local pulmonary inflammatory activity; this may outweigh the beneficial systemic anti-inflammatory action of VNS. Organ/function-specific therapy can be achieved by imaging of localized fascicle activity within the vagus nerve and selective stimulation of identified organ-specific fascicles. This may be able to provide selective neuromodulation of different pathways within the vagus nerve and offer a novel means to improve outcome in ARDS. This has motivated this review in which we discuss the mechanisms of anti-inflammatory effects of VNS, progress in selective VNS techniques, and a possible application for ARDS.

Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat.

It is necessary to understand the morphology of the vagus nerve (VN) to design and deliver effective and selective vagus nerve stimulation (VNS) because nerve morphology influences fiber responses to electrical stimulation. Specifically, nerve diameter (and thus, electrode-fiber distance), fascicle diameter, fascicular organization, and perineurium thickness all significantly affect the responses of nerve fibers to electrical signals delivered through a cuff electrode. We quantified the morphology of cervical and subdiaphragmatic VNs in humans, pigs, and rats: effective nerve diameter, number of fascicles, effective fascicle diameters, proportions of endoneurial, perineurial, and epineurial tissues, and perineurium thickness. The human and pig VNs were comparable sizes (∼2 mm cervically; ∼1.6 mm subdiaphragmatically), while the rat nerves were ten times smaller. The pig nerves had ten times more fascicles—and the fascicles were smaller—than in human nerves (47 vs. 7 fascicles cervically; 38 vs. 5 fascicles subdiaphragmatically). Comparing the cervical to the subdiaphragmatic VNs, the nerves and fascicles were larger at the cervical level for all species and there were more fascicles for pigs. Human morphology generally exhibited greater variability across samples than pigs and rats. A prior study of human somatic nerves indicated that the ratio of perineurium thickness to fascicle diameter was approximately constant across fascicle diameters. However, our data found thicker human and pig VN perineurium than those prior data: the VNs had thicker perineurium for larger fascicles and thicker perineurium normalized by fascicle diameter for smaller fascicles. Understanding these differences in VN morphology between preclinical models and the clinical target, as well as the variability across individuals of a species, is essential for designing suitable cuff electrodes and stimulation parameters and for informing translation of preclinical results to clinical application to advance the therapeutic efficacy of VNS.

Selective Stimulation of Vagal Pathways Using a Multi‐contact Circumferential Cuff Electrode

Vagus nerve stimulation (VNS) has been used to treat epileptic seizures, depression, cardiovascular disease, and obesity; however, non‐selective vagal stimulation can produce adverse side effects, such as nausea and reduced blood pressure. The current study was designed to assess the potential for a precision, multi‐contact nerve cuff electrode to produce selective and discrete activation of vagus nerve fibers. We used an acute anesthetized ferret preparation (n = 6) to test the effects of an abdominal vagus nerve electrode (Micro‐Leads Neuro) on cellular responses (compound action potential, CAP) recorded from a 32‐channel microelectrode array (MEA) inserted into the nodose ganglion. We investigated the selectivity of nodose responses by varying: (1) electrode contact stimulation pair; (2) pulse width, using 0.1, 0.5, and 1.0 ms; and (3) pulse amplitude, steps of 20 μA. Stimulation was delivered at 2 Hz using the average response from 120 pulses per trial. Selectivity was quantified by the number of MEA channels responding to only one of the two cuff stimulation pairs. Across all animals, stimulation selectively evoked responses recorded by multiple different contacts in the MEA. In a similar experimental setup in three additional animals, multi‐contact stimulation of the abdominal vagus was used to drive changes in gastric myoelectric activity (GMA), as assessed by a set of four to six 4‐contact electrode planar arrays (Micro‐Leads Neuro) sutured to the serosal surface of the stomach. In one animal, selective stimulation drove changes in GMA without a concomitant change in heart rate (HR) or respiration rate (RR), while in two other animals, there was a selective change in HR or RR without a change in GMA. The present study supports the viability of producing selective responses from multi‐contact abdominal vagus nerve cuff electrodes and suggests the need to further investigate the effects of selective VNS on end‐organ therapeutic and off‐target effects, such as gastrointestinal motility, heart rate, blood pressure, inflammatory responses, and metabolic effects (e.g., blood cytokine levels and insulin release).Support or Funding InformationThis research was supported by funding from the NIH SPARC Common Fund Program (award #U18TR002205).

MicroCT optimisation for imaging fascicular anatomy in peripheral nerves

BackgroundDue to the lack of understanding of the fascicular organisation, vagus nerve stimulation (VNS) leads to unwanted off-target effects. Micro-computed tomography (microCT) can be used to trace fascicles from periphery and image fascicular anatomy. New methodIn this study, we present a simple and reproducible method for imaging fascicles in peripheral nerves with iodine staining and microCT for the determination of fascicular anatomy and organisation. ResultsAt the determined optimal pre-processing steps and scanning parameters, the microCT protocol allowed for segmentation and tracking of fascicles within the nerves. This was achieved after 24 hours and 120 hours of staining with Lugol’s solution (1% total iodine) for rat sciatic and pig vagus nerves, respectively, and the following scanning parameters: 4 μm voxel size, 35 kVp energy, 114 μA current, 4 W power, 0.25 fps in 4 s exposure time, 3176 projections and a molybdenum target. Comparison with existing method(s)This optimised method for imaging fascicles provides high-resolution, three-dimensional images and full imaging penetration depth not obtainable with methods typically used such as histology, magnetic resonance imaging and optical coherence tomography whilst obviating time-consuming pre-processing methods, the amount of memory required, destruction of the samples and the cost associated with current microCT methods. ConclusionThe optimised microCT protocol facilitates segmentation and tracking of the fascicles within the nerve. The resulting segmentation map of the functional anatomical organisation of the vagus nerve will enable selective VNS ultimately allowing for the avoidance of the off-target effects and improving its therapeutic efficacy.

Effect of Cardiac-Cycle-Synchronized Selective Vagal Stimulation on Heart Rate and Blood Pressure in Rats.

Activation of the baroreflex system through the selective vagal nerve stimulation (sVNS) may become a treatment option for therapy-resistant hypertension, which is a frequently observed problem in the antihypertensive therapy. In previous studies, we used continuous sVNS to lower blood pressure (BP) without major side effects in a rat model. As continuous stimulation is energy consuming and sVNS could be implemented in an antihypertensive stimulator, it was the aim of this study to investigate the efficacy of pulsatile, cardiac-cycle-synchronized sVNS (cssVNS) on the reduction of BP. A multichannel cuff electrode was wrapped around the left vagal nerve in six male Wistar rats under Isoflurane anesthesia. BP was recorded in the left carotid artery. An electrocardiogram (ECG) was obtained via subcutaneous needle electrodes. The aortic depressor nerve fibers in the vagal nerve bundle were selectively stimulated with 18 parameter settings within a window of 15-30ms after the R-peak in the ECG. The stimulation paradigm included every heartbeat, every second heart beat, and every third heart beat. BP and heart rate were initially recorded over 10min. Using cssVNS, BP could be significantly reduced over 30min and maintained at this level. While the highest BP reduction was seen during cssVNS at every heartbeat with minimal bradycardia, less-yet significant-BP reduction was seen during cssVNS at every second or third heartbeat without causing detectable bradycardia. cssVNS can chronically reduce BP in rats avoiding measurable bradycardic side effects. This energy-efficient technique might allow the implementation of sVNS using an implantable device to permanently lower BP in patients. The study was funded by Bundesministerium fur Bildung und Forschung/German Federal Ministry of Education and Research among the call "Individualisierte Medizintechnik" under the grant number FKZ 13GW0120B.

Haemodynamic Responses to Selective Vagal Nerve Stimulation under Enalapril Medication in Rats.

Selective vagal nerve stimulation (sVNS) has been demonstrated to lower blood pressure (BP) in rats without causing major side effects. This method might be adapted for the treatment of therapy-resistant hypertension in patients. Converting enzyme inhibitors (CEIs) are among the first drugs that are administered for arterial hypertension and prominently reduce BP primarily by interacting with the renin-angiotensin system of the kidneys. Beyond the reduction of BP, CEI have a positive effect on the survival rate after myocardial infarction; they reduce the rates of stroke and improve the neurohormonal status in heart-failure patients. If sVNS might be introduced as a therapy against resistant hypertension, patients will at least partially stay on their CEI medication. It is therefore the aim of this study to investigate the influence of the CEI enalapril on the haemodynamic and respiratory effects of sVNS. In 10 male Wistar rats, a polyimide-based multichannel-cuff-electrode was placed around the vagal nerve bundle to selectively stimulate the aortic depressor nerve fibres. Stimulation parameters were adapted to the thresholds of the individual animals and included repetition frequencies between 30 and 50 Hz, amplitudes of 0.5 to 1.5 mA and pulse widths between 0.4 ms and 1.0 ms. BP responses were detected with a microtip transducer in the left carotid artery, and electrocardiography was recorded with subcutaneous electrodes. After intravenous administration of enalapril (2 mg/kg bodyweight), the animals’ mean arterial blood pressures (MAPs) decreased significantly, while the heart rates (HRs) were not significantly influenced. The effects of sVNS on BP and HR were attenuated by enalapril but were still present. We conclude that sVNS can lower the MAP during enalapril treatment without relevant side effects.

Effect of selective vagal nerve stimulation on blood pressure, heart rate and respiratory rate in rats under metoprolol medication.

Selective vagal nerve stimulation (sVNS) has been shown to reduce blood pressure without major side effects in rats. This technology might be the key to non-medical antihypertensive treatment in patients with therapy-resistant hypertension. β-blockers are the first-line therapy of hypertension and have in general a bradycardic effect. As VNS itself can also promote bradycardia, it was the aim of this study to investigate the influence of the β1-selective blocker Metoprolol on the effect of sVNS especially with respect to the heart rate. In 10 male Wistar rats, a polyimide multichannel-cuff electrode was placed around the vagal nerve bundle to selectively stimulate the aortic depressor nerve fibers. The stimulation parameters were adapted to the thresholds of individual animals and were in the following ranges: frequency 30-50 Hz, amplitude 0.3-1.8 mA and pulse width 0.3-1.3 ms. Blood pressure responses were detected with a microtip transducer in the carotid artery, and electrocardiography was recorded with s.c. chest electrodes. After IV administration of Metoprolol (2 mg kg(-1) body weight), the animals' mean arterial blood pressure (MAP) and heart rate (HR) decreased significantly. Although the selective electrical stimulation of the baroreceptive fibers reduced MAP and HR, both effects were significantly alleviated by Metoprolol. As a side effect, the rate of stimulation-induced apnea significantly increased after Metoprolol administration. sVNS can lower the MAP under Metoprolol without causing severe bradycardia.

Electrochemical and Electrophysiological Performance of Platinum Electrodes Within the Ninety-Nine-Electrode Stimulating Nerve Cuff.

The trend in neural prostheses using selective nerve stimulation for electrical stimulation therapies is headed toward single-part systems having a large number of working electrodes (WEs), each of which selectively stimulate neural tissue or record neural response (NR). The present article reviews the electrochemical and electrophysiological performance of platinum WE within a ninety-nine-electrode spiral cuff for selective nerve stimulation and recording of peripheral nerves, with a focus on the vagus nerve (VN). The electrochemical properties of the WE were studied in vitro using the electrochemical impedance spectroscopy (EIS) technique. The equivalent circuit model (ECM) of the interface between the WE and neural tissue was extracted from the EIS data and simulated in the time domain using a preset current stimulus. Electrophysiological performance of in-space and fiber-type highly selective vagus nerve stimulation (VNS) was tested using an isolated segment of a porcine VN and carotid artery as a reference. A quasitrapezoidal current-controlled pulse (stimulus) was applied to the VN or arterial segment using an appointed group of three electrodes (triplet). The triplet and stimulus were configured to predominantly stimulate B-fibers and minimize the stimulation of A-fibers. The EIS results revealed capacitive charge transfer predominance, which is a highly desirable property. Electrophysiological performance testing indicated the potential existence of certain parameters and waveforms of the stimulus for which the contribution of the A-fibers to the NR decreased slightly and that of the B-fibers increased slightly. Findings show that the design of the stimulating electrodes, based on the EIS and ECM results, could act as a useful tool for nerve cuff development.

Blood pressure control with selective vagal nerve stimulation and minimal side effects

Objective. Hypertension is the largest threat to patient health and a burden to health care systems. Despite various options, 30% of patients do not respond sufficiently to medical treatment. Mechanoreceptors in the aortic arch relay blood pressure (BP) levels through vagal nerve (VN) fibers to the brainstem and trigger the baroreflex, lowering the BP. Selective electrical stimulation of these nerve fibers reduced BP in rats. However, there is no technique described to localize and stimulate these fibers inside the VN without inadvertent stimulation of non-baroreceptive fibers causing side effects like bradycardia and bradypnea. Approach. We present a novel method for selective VN stimulation to reduce BP without the aforementioned side effects. Baroreceptor compound activity of rat VN (n = 5) was localized using a multichannel cuff electrode, true tripolar recording and a coherent averaging algorithm triggered by BP or electrocardiogram. Main results. Tripolar stimulation over electrodes near the barofibers reduced the BP without triggering significant bradycardia and bradypnea. The BP drop was adjusted to 60% of the initial value by varying the stimulation pulse width and duration, and lasted up to five times longer than the stimulation. Significance. The presented method is robust to impedance changes, independent of the electrode's relative position, does not compromise the nerve and can run on implantable, ultra-low power signal processors.

Alternative Paradigm of Selective Vagus Nerve Stimulation Tested on an Isolated Porcine Vagus Nerve

Alternative paradigm for spatial and fibre-type selective vagus nerve stimulation (VNS) was developed using realistic structural topography and tested in an isolated segment of a porcine cervical left vagus nerve (LVN). A spiral cuff (cuff) containing a matrix of ninety-nine electrodes was developed for selective VNS. A quasitrapezoidal stimulating pulse (stimulus) was applied to the LVN via an appointed group of three electrodes (triplet). The triplet and stimulus were configured to predominantly stimulate the B-fibres, minimizing stimulation of the A-fibres and by-passing the stimulation of the C-fibres. To assess which fibres made the most probable contribution to the neural response (NR) during selective VNS, the distribution of conduction velocity (CV) within the LVN was considered. Experimental testing of the paradigm showed the existence of certain parameters and waveforms of the stimulus, for which the contribution of the A-fibres to the NR was slightly reduced and that of the B-fibres was slightly enlarged. The cuff provided satisfactory fascicle discrimination in selective VNS as well as satisfactory fascicle discrimination during NR recording. However, in the present stage of development, fibre-type VNS remained rather limited.

Frequency dependent effect of selective biphasic left vagus nerve stimulation on heart rate and arterial pressure

Activation of the parasympathetic pathway leads to negative chronotropic, dromotropic, and inotropic changes of heart function. The ability to selectively stimulate certain superficial compartments of peripheral nerves has been demonstrated previously. The aim of the present study was to find a clinically acceptable selective biphasic vagus nerve stimulation technique, which could allow gradual regulation of heart rate and systemic arterial pressure. In two patients, the left vagus nerve was stimulated with a combination of quasi-trapezoidal cathodic and rectangular anodic current pulses with different stimulation frequencies (10Hz, 20Hz, 30Hz) and increasing current. The heart rate and systemic arterial pressure decreased with increasing current at all different stimulation frequencies (p<0.05). The heart rate and arterial pressure response was more gradual with 10Hz compared to 20Hz/30Hz vagus nerve stimulation (p<0.05). In conclusion, selective vagus nerve stimulation, with a combination of quasi-trapezoidal cathodic and rectangular anodic current pulses at 10Hz, offers gradual heart rate and systolic arterial pressure control.

Frank-Starling mechanism contributes modestly to ventricular performance during atrial fibrillation

The aim of this study was to assess whether Frank-Starling mechanism has an independent effect on left ventricular (LV) performance in atrial fibrillation (AF). Ventricular performance in AF depends on variable contractility through the interval-force mechanism based on the ratio of preceding and pre-preceding RR intervals (RR(p)/RR(pp)). The impact of end-diastolic volume (EDV) variability, through the Frank-Starling mechanism, is not well understood. We induced AF in 16 open chest dogs. RR intervals, LV pressure, LV volume, and aortic flow were collected for >400 beats during rapid AF (ventricular cycle length 292 +/- 66 ms). In six of the dogs, additional data were collected while average ventricular cycle length was prolonged from 258 +/- 34 ms to 445 +/- 80 ms by selective vagal nerve stimulation of the AV node. The relations of maximal LV power (LVPower) and peak LV pressure derivative (dP/dt) versus RR(p)/RR(pp) were fitted to the equation y = A * (1 - EXP (RR(p)/RR(pp)min - RR(p)/RR(pp))/C) and the residuals (RES) of these relations were analyzed. LVPower and dP/dt strongly correlated with RR(p)/RR(pp) (r(2) = 0.67 +/- 0.12 and 0.66 +/- 0.12, P < .0001 for all correlations). Importantly, RES-LVPower and RES-dP/dt showed linear correlation with EDV (r(2) = 0.20 +/- 0.14 and r(2) = 0.24 +/- 0.17, P < .01 for all correlations). In the six dogs with slowed average ventricular rate, the slope of both residual relationships (RES-LVPower vs EDV and RES- dP/dt vs EDV) decreased (P < .03 for both). The Frank-Starling mechanism contributes to ventricular performance in AF independently of the interval-force effects of the beat-to-beat variability in cardiac contractility. The Frank-Starling mechanism is sensitive to the average ventricular rate.

Selective AV nodal vagal stimulation improves hemodynamics during acute atrial fibrillation in dogs.

Although the atrioventricular node (AVN) plays a vital role in blocking many of the atrial impulses from reaching the ventricles during atrial fibrillation (AF), a rapid irregular ventricular rate nevertheless persists. The goals of the present study were to explore the feasibility of novel epicardial selective vagal nerve stimulation for slowing of the ventricular rate during AF and to characterize the hemodynamic benefits in vivo. Electrophysiological-echocardiographic experiments were performed on 11 anesthetized open-chest dogs. Hemodynamic measurements were performed during three distinct periods: 1) sinus rate, 2) AF, and 3) AF with vagal nerve stimulation. AF was associated with significant deterioration of all measured parameters (P < 0.025). The vagal nerve stimulation produced slowing of the ventricular rate, significant reversal of the pressure and contractile indexes (P < 0.025), and a sharp reduction in one-half of the abortive ventricular contractions. The present study provides comprehensive evidence that slowing of the ventricular rate during AF by selective ganglionic stimulation of the vagal nerves that innervate the AVN successfully improved the hemodynamic responses.