Vagal stimulation and cardiac chronotropy in rats.

Increasing frequencies of electrical stimulation of the right vagus nerve in the rat yielded a progressive lengthening of heart periods. Stimulation was capable of driving vagal control of cardiac chronotropy over its full physiological dynamic range, to the point of sinus block. The steady-state transfer function between vagal stimulation frequency and cardiac chronotropy was approximately linear, with a slope of 7.4 ms/Hz. The linearity of the stimulation-heart period function is consistent with previous reports in dogs, rabbits and humans, although the slope of the function was considerably lower in the rat.     

Vagal nerve stimulation in children

Vagal nerve stimulation is a new therapeutic option for patients with medically refractory epilepsy. The FDA approved the NeuroCybernetic Prosthesis (NCP) in July 1997 for use in adults and adolescents over the age of 12 years with medically refractory epilepsy. Most of the patients in the initial pilot studies and subsequent extended longitudinal and randomized controlled studies were adults. There were small numbers of children who received the NCP system. However, these were not part of controlled studies. As the system has had greater exposure in the United States and Europe, there are more children who are receiving vagal nerve stimulation (VNS). Initial data from open-label, uncontrolled studies suggest that VNS does have some efficacy and safety for those children with refractory epilepsy who have not responded to appropriate trials of antiepileptic drugs. The questions to be asked and answered are as follows: (1) When is a child medically refractory? (2) What are the criteria for selection for VNS? (3) Which seizure types or syndromes will benefit most from the treatment? and (4) What are the most effective and safe stimulation parameters, and do these vary depending on the seizure type?     

Vagal nerve stimulation induces intermittent hypocapnia

PURPOSE: To study whether respiratory alteration caused by vagal nerve stimulation (VNS) can change end-tidal carbon dioxide (EtCO2) levels. METHODS: We performed polygraphic recordings including capnographic monitoring during daytime sleep on adults with VNS therapy. RESULTS: Ten of 13 patients showed VNS-induced alterations in the frequency or amplitude of respiration. Five patients had a consistent increase in respiratory rate with a simultaneous, consistent and significant decrease (p < 0.01; 5-22%) in EtCO2 during VNS. Three subjects showed occasional decreases in EtCO2 during VNS, and two showed no clearly detectable VNS-related EtCO2 changes. CONCLUSIONS: Our findings suggest that VNS may alter brain CO2 levels through changes in respiration. Because carbon dioxide (CO2) has potent effects on various brain functions, it is possible that these transient CO2 changes may have an effect on the state transitions between interictal and preictal states.     

Vagal nerve stimulation as a treatment of epilepsy

INTRODUCTION: Vagus nerve stimulation (VNS) is a non-pharmacological treatment for drug resistant epilepsy. STATE OF ART: The good efficacy and tolerability of this device is now well established after several controlled studies, and more than 17000 people operated on in different countries. The physiology of VNS is not yet well known, and the potential mechanisms of action are reviewed. VNS seems to be as efficient as a new medication without some of the disadvantages (in case of pregnancy for example). SNV may have a beneficial effect for all kinds of drug-resistant epilepsy. PERSPECTIVES: Better knowledge of the underlying anti-epileptic mechanisms may help to select the better responders to this expensive anti-epileptic tool.     

Vagal nerve stimulation does not unkindle seizures.

The purpose of this study was to investigate a mechanism of action for the effect of vagal nerve stimulation on reducing seizures in patients with complex partial epilepsy. The hypothesis tested was that vagal nerve stimulation has an antikindling effect on epilepsy. The databases of two large clinical trials (E03, E05) were accessed, and statistical methods were applied using logarithmic transforms and regression analysis. Two parameters--duration of a patient's epilepsy before entering the clinical trial and the patient's seizure density before entering the clinical trial--were used as markers of subsequent seizure control during vagal nerve stimulation. In general, there was not a good fit to the regression lines, and the slope of the lines did not conform to the hypothesis. The hypothesis that vagal nerve stimulation may unkindle epileptic seizures was not supported.     

Vagal nerve stimulation in tuberous sclerosis complex patients

This is an open-label, retrospective, multicenter study to determine the outcome of intermittent stimulation of the left vagal nerve in children with tuberous sclerosis complex and medically refractory epilepsy. The records of all children treated with vagal nerve stimulation were reviewed in five pediatric epilepsy centers to locate those with tuberous sclerosis complex who had been treated with vagal nerve stimulation for at least 6 months. These patients were compared with (1) a series of patients obtained from the literature, (2) 10 similar control patients with epilepsy obtained from a registry of patients receiving vagal nerve stimulation, and (3) four published series of tuberous sclerosis complex patients whose epilepsy was surgically managed. Ten tuberous sclerosis complex patients with medically refractory epilepsy treated with vagal nerve stimulation were found. Nine experienced at least a 50% reduction in seizure frequency, and half had a 90% or greater reduction in seizure frequency. No adverse events were encountered. Comparison with published and registry patients revealed improved seizure control in the tuberous sclerosis complex patients. Comparison with the group undergoing seizure surgery demonstrated improved outcomes after surgery. Vagal nerve stimulation appears to be an effective and well-tolerated adjunctive therapy in patients with tuberous sclerosis complex and seizures refractory to medical therapy. Resective surgery has a better prospect for improved seizure control.     

Vagal nerve stimulation improves cerebellar tremor and dysphagia in multiple sclerosis

Vagus nerve stimulation (VNS), an adjunctive approach for the treatment of epilepsy, was performed in three multiple sclerosis (MS) patients displaying postural cerebellar tremor (PCT) and dysphagia. Following VNS, improvement of PCT and dysphagia was manifested over a period of two and three months, respectively. In view of the involvement of the main brainstem visceral component of the vagus, the nucleus tractus solitarius (NTS), in modulating central pattern generators (CPGs) linked to both olive complex pathway and swallowing, improvement is likely to be VNS related. The results obtained suggest an additional therapeutic application for VNS and may represent a novel form of treatment in patients with severe MS.     

Vagal nerve stimulation: adjustments to reduce painful side effects

Vagal nerve stimulation is an approved adjunctive treatment for medically intractable epilepsy. Although it is generally well tolerated, some patients experience pain, coughing, or hoarseness during stimulation. Lowering the pulse width in these patients alleviates pain and reduces voice alteration without loss of efficacy. This allows more optimal programming of stimulation intensities.     

Vagal nerve stimulation: relationship between outcome and electroclinical seizure pattern.

In recent years, vagal nerve stimulation (VNS) has been proposed as a possible way to improve the control of refractory (partial and generalized) seizures. To date, however, there is no complete understanding of the underlying mechanism for this action nor are there any available guidelines or criteria for the selection of those candidates that might be most suitable for this kind of neuromodulating surgery. This report presents evidence that should be helpful in defining the clinical criteria for using VNS for the treatment of refractory seizures. We report on 17 patients with severe partial refractory epilepsy and polymorphous seizures, who have been operated on previously or who were excluded from epilepsy surgery and for whom, at least, one seizure type has been electrographically recorded. Sixteen of these patients also had falling seizures. Our objective was to identify responders and to correlate the outcome of their seizures with the EEGraphic onset of their seizure. Follow-up ranged from 4 to 9 years. The results of this study indicate a significant reduction of seizures in only four patients and better outcome in patients where the onset of seizure activity occurred in the temporal area. Patients with frontal or frontocentral seizures resulted in the poorest outcomes. In four patients with Lennox-Gastaut syndrome VNS produced no significant reduction of seizures, while falling seizures decreased significantly in three patients with retropulsive falls. These results of this small series of patients suggest that VNS might be more suitable in patients with temporal rather than frontal or central seizure onset. Further studies are required to support this hypothesis.     

Vagal stimulation by manual carotid sinus massage to acutely suppress seizures

Carotid sinus massage, a technique involving digital pressure on the richly innervated carotid sinus, is a time-honoured method for termination of supraventricular tachycardia due to paroxysmal atrial tachycardia. Vagal nerve stimulation, a more recent technique, employs pacemaker stimulation of the vagus as a treatment for refractory epilepsy. This case report discusses the use of carotid sinus massage to abort seizure activity. The patient used manual manipulation of the carotid sinus (similar to cardiology techniques) to suppress seizures, achieving a therapeutic neurological outcome.     

Vagal nerve stimulation during muscarinic and beta-adrenergic blockade causes significant coronary artery dilation

Vasoactive intestinal peptide (VIP) is present in post-ganglionic vagal nerve fibers in the coronary arteries and right ventricle but no significant amounts are found in the left ventricle. We determined the effects of VIP, released endogenously from cardiac vagal nerves, on the circumflex mean coronary artery pressure and on right and left ventricular (RV and LV) contractility (dP/dt_max) and relaxation (dP/dt_min). In 20 anesthetized, open chest mongrel dogs, the cervical vagus nerves and cardiac sympathetic ansa subclaviae were isolated and transected. Electrodes were applied to the cardiac segments of the right and left vagus nerves for subsequent stimulation. The muscarinic and β-adrenergic receptors were blocked with atropine and propranolol, respectively. The heart rate was controlled by either producing atrioventricular node block in 10 dogs and pacing the ventricles (series 1) or by right atrial pacing in 10 separate dogs (series 2). Coronary artery blood flow was controlled by perfusing the circumflex coronary artery in each dog with femoral arterial blood at a controlled flow rate. Coronary artery pressure, ventricular and aortic pressures and dP/dt were continuously measured. Experiments were performed prior to and after the administration of [4Cl-D-Phe⁶,Leu¹⁷]VIP, a sensitive and selective VIP antagonist. Vagal nerve stimulation at 20 Hz (0.5 ms, 20 V) for 5 min significantly decreased the circumflex mean coronary artery pressure by 17% from the control value of 95±2 mmHg in series 1 and by 13% from the control value of 109±2 mmHg in series 2 (both p<0.005). Aortic, LV and RV systolic and end-diastolic pressures, LV dP/dt_max and dP/dt_min, and the EKG did not change. In contrast, RV dP/dt_max and dP/dt_min increased by 22% (p<0.04) and 23% (p<0.02), respectively, in series 1 and by 26% (p<0.02) and 33% (p<0.01), respectively, in series 2. The VIP antagonist, [4Cl-D-Phe⁶,Leu¹⁷]VIP, directly injected into the left circumflex coronary artery, had no effect on coronary, aortic or ventricular pressures, ventricular dP/dt or the EKG. However, 20 Hz vagal stimulation in the presence of the VIP antagonist did not decrease circumflex mean coronary artery pressure. In addition, vagal stimulation, in the presence of the VIP antagonist, had no effect on LV pressures or dP/dt but increased RV dP/dt_max and dP/dt_min. RV dP/dt_max increased by 16% (p<0.01) and RV dP/dt_min increased by 22% (p<0.04), respectively, in series 1 and by 27 and 24%, respectively, in series 2 (both p<0.01). Vagal nerve stimulation during muscarinic and β-adrenergic blockade releases VIP or a `VIP-like' substance that significantly decreases circumflex coronary artery vascular resistance and increases RV dP/dt_max and dP/dt_min.     

Vagal nerve stimulation for drug-resistant epilepsies in different age, aetiology and duration

Purpose  

The aim of the study was to compare the outcome with respect to age of implant, aetiology and duration of epilepsy.     

Vagal stimulation during muscarinic and beta-adrenergic blockade increases atrial contractility and heart rate.

We determined the effects of continuous cardiac vagal nerve stimulation on atrial contractility and on heart rate in mongrel dogs in which we blocked the muscarinic and beta-adrenergic receptors. Each dog received atropine, 0.5 mg/kg and propranolol, 0.5-1 mg/kg. We stimulated the cardiac vagus nerves in each dog for three separate 5-min periods at frequencies of 0 (control), 20, and 40 Hz (5 ms, 15 V) and measured the changes in atrial contractility and heart rate. Vagal nerve stimulation increased right atrial contractility from the control value by 27% at 20 Hz and by 19% during stimulation at 40 Hz (P < 0.001). Vagal nerve stimulation also increased the heart rate from 114 +/- 5 beats/min during the control period to 146 +/- 10 beats/min (P < 0.01) during stimulation at a frequency of 20 Hz and to 140 +/- 11 beats/min (P < 0.05) during stimulation at 40 Hz. Injection of the vasoactive intestinal peptide (VIP) antagonist, [4Cl-D-Phe6,Leu17]VIP, directly into the dog right coronary artery in concentrations of 0 (control), 2, and 4 micrograms/kg did not influence spontaneous atrial contractility or the heart rate. However, 4 micrograms/kg of the VIP antagonist significantly reduced the augmentation in right atrial contractility and the increase in heart rate during vagal nerve stimulation. Our experiments suggest that cardiac vagal nerve stimulation, during muscarinic and beta-adrenergic receptor blockade, releases VIP or a 'VIP-like substance', that significantly augments atrial contractility and increases heart rate.     

Vagal action on atrioventricular conduction and its inhibition by sympathetic stimulation and neuropeptide Y in anaesthetised dogs

The observed change in atrioventricular conduction time (PR interval) in response to vagal stimulation is the result of two opposing effects; PR interval increases in response to the direct action of the vagus on atrioventricular nodal cells (direct effect), and the accompanying slowing of heart rate acts to decrease PR interval (indirect effect). The relationships between these opposing effects were studied in anaesthetised dogs. This study has shown that the increase in PR interval in response to vagal stimulation is well correlated with vagal stimulation frequency and can be regarded as linear. This is so for unpaced and paced hearts. We have also shown there is an increase in the sensitivity of the relationship between increase in PR interval and vagal stimulation frequency during pacing. This increase in sensitivity is attributable to the elimination of the indirect effect of the slowing of heart rate. During atrial pacing, the relationship between pulse interval and PR interval resembles a hyperbola. At low-pulse intervals (i.e. fast heart rates) the PR interval increases. This is in agreement with previous qualitative findings and is related to the functional refractory period of the atrioventricular cells. The action of sympathetic stimulation and injection of neuropeptide Y has not been studied previously. The vagally induced increase in atrioventricular conduction time is attenuated for many minutes following stimulation of the cardiac sympathetic nerve at 16 Hz for 2 min or by intravenous injection of neuropeptide Y (25-50 micrograms/kg). Stimulation of the right cardiac sympathetic nerve evokes a significantly stronger inhibition of the vagally induced prolongation of pulse interval than stimulation of the left sympathetic nerve. On the other hand, stimulation of the left or right sympathetic nerves cause similar inhibition of vagal action on atrioventricular conduction time.     

Tertiapin-Q removes a large and rapidly acting component of vagal slowing of the guinea-pig cardiac pacemaker

The participation of acetylcholine-activated potassium current (I_K,ACh) and hyperpolarization-activated pacemaker current (I_f) in vagal bradycardia were examined using vagally-innervated preparations of guinea-pig atria. Preparations were maintained in Krebs–Henseleit solution (36 °C). Before treatment, trains of vagal stimuli (10 s at 2, 5 and 10 Hz) produced graded bradycardias displaying rapid onset and offset. Tertiapin-Q (300 nM), which blocks I_K,ACh, had no effect on baseline atrial rate. In tertiapin-Q, vagal bradycardia displayed a gradual onset and offset, with a peak response ~ 50% of that recorded in control conditions. Cumulative addition of 1 mM ZD7288 (blocker of I_f) caused atrial rate to fall by ~ 60%, but had no further effect on the amplitude of the vagal bradycardia, while response onset and offset became slightly faster. From these observations, we argue that (i) vagal bradycardia was attributable primarily to activation of I_K,ACh, (ii) vagal modulation of I_f had a minor influence on the rate of onset and offset of bradycardia, and (iii) removal of the influence of I_K,ACh unmasked a slow response, of undetermined origin, to vagal stimulation. In a separate set of experiments we compared the effects of 1 mM Ba²⁺ and 300 nM tertiapin-Q on vagal bradycardia. Ba²⁺ reduced baseline atrial rate and the response to vagal stimulation. Subsequent cumulative addition of tertiapin-Q had no additional effect on baseline atrial rate, but caused further reduction in the amplitude of vagal bradycardia, suggesting that 1 mM Ba²⁺ did not achieve a complete block of I_K,ACh in this preparation.     

Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects

Vagal nerve stimulation (VNS) is an approved treatment for epilepsy and is currently under investigation as a therapy for other disorders, including depression, anxiety and Alzheimer's disease. This review examines the pre-clinical and clinical literature relating to VNS. A brief historical perspective is given, followed by consideration of the efficacy of the various clinical applications of VNS. Finally, what is known about the mechanism by which VNS exerts clinical benefit is considered. It is concluded that although the precise mechanism of action of VNS is still unknown, the search for the mechanism has the potential to lend new insight into the neuropathology of depression. It is important that prior assumptions about the influence of VNS on particular aspects of brain function do not constrain the investigations.