Left Thoracic Vagus Research Articles

Transcutaneous Auricular Vagus Nerve Stimulation.

Invasive vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. Besides recognized clinical efficacy in about 60% of patients, there are major drawbacks such as invasiveness and common side effects including hoarseness, sore throat, shortness of breath, and coughing. Invasive VNS applies electrical stimulation to the left cervical branch of the vagus nerve and excites thick-myelinated afferent nerve fibers. Peripheral vagus nerve afferent volley initiates brainstem activity in the nucleus of the solitary tract and provokes typical brainstem and cerebral activation patterns that mediate the anticonvulsive mode of action. Whereas invasive VNS is an established neuromodulatory treatment in drug-resistant epilepsy, transcutaneous VNS (tVNS) of the auricular branch of the vagus nerve is suggested to be an alternative access path to the same neuronal network without invasiveness. Preclinical and clinical studies indicate that especially the cymba conchae of the auricle is selectively supplied by the auricular branch of the vagus nerve. Recent anatomical data demonstrate existence and quantity of thick-myelinated afferent nerve fibers of the left auricular branch of the vagus nerve that carries 21% of thick-myelinated afferent nerve fibers counted in the left thoracic vagus nerve in humans. Projection of auricular branch of the vagus nerve afferents from the auricle to the nucleus of the solitary tract is known from histochemical and electrophysiological experiments in rodents and confirmed in humans by functional imaging. Cerebral activation patterns triggered by invasive and tVNS resemble each other in appearance. Clinical trials in patients address safety and performance of tVNS and provide evidence for application in drug-resistant epilepsy.

Sympathetic nerve fibers in human cervical and thoracic vagus nerves.

Vagus nerve stimulation (VNS) therapy has been used for chronic heart failure and is believed to improve imbalance of autonomic control by increasing parasympathetic activity. Although it is known that there is neural communication between the VN and the cervical sympathetic trunk, there are few data regarding the quantity and/or distribution of the sympathetic components within the vagus nerve (VN). To examine the sympathetic components within the human VN and correlate them with the presence of cardiac and neurologic diseases. We performed immunohistochemistry on 31 human cervical and thoracic VNs (total 104 VNs) from autopsies and reviewed the patients' records. We correlated the quantity of sympathetic nerve fibers within the VNs with cardiovascular and neurologic disease states. All 104 VNs contain tyrosine hydroxylase (TH)-positive (sympathetic) nerve fibers; the mean TH-positive areas were 5.47% in the right cervical VN, 3.97% in the left cervical VN, 5.11% in the right thoracic VN, and 4.20% in the left thoracic VN. The distribution of TH-positive nerve fibers varied from case to case: central, peripheral, or scattered throughout nerve bundles. No statistically significant differences in nerve morphology were seen between diseases in which VNS is considered effective (depression and chronic heart failure) and other cardiovascular diseases or neurodegenerative disease. Human VNs contain sympathetic nerve fibers. The sympathetic component within the VN could play a role in physiologic effects reported with VNS. The recognition of sympathetic nerve fibers in the VNs may lead to better understanding of the therapeutic mechanisms of VNS.

C-Fos expression in rat brain stem and spinal cord in response to activation of cardiac ischemia-sensitive afferent neurons and electrostimulatory modulation.

The purpose of this study was to identify central neuronal sites activated by stimulation of cardiac ischemia-sensitive afferent neurons and determine whether electrical stimulation of left vagal afferent fibers modified the pattern of neuronal activation. Fos-like immunoreactivity (Fos-LI) was used as an index of neuronal activation in selected levels of cervical and thoracic spinal cord and brain stem. Adult Sprague-Dawley rats were anesthetized with urethane and underwent intrapericardial infusion of an "inflammatory exudate solution" (IES) containing algogenic substances that are released during ischemia (10 mM adenosine, bradykinin, prostaglandin E2, and 5-hydroxytryptamine) or occlusion of the left anterior descending coronary artery (CoAO) to activate cardiac ischemia-sensitive (nociceptive) afferent fibers. IES and CoAO increased Fos-LI above resting levels in dorsal horns in laminae I-V at C2 and T4 and in the caudal nucleus tractus solitarius. Dorsal rhizotomy virtually eliminated Fos-LI in the spinal cord as well as the brain stem. Neuromodulation of the ischemic signal by electrical stimulation of the central end of the left thoracic vagus excited neurons at the cervical and brain stem level but inhibited neurons at the thoracic spinal cord during IES or CoAO. These results suggest that stimulation of the left thoracic vagus excites descending inhibitory pathways. Inhibition at the thoracic spinal level that suppresses the ischemic (nociceptive) input signal may occur by a short-loop descending pathway via signals from cervical propriospinal circuits and/or a longer-loop descending pathway via signals from the nucleus tractus solitarius.

Vagus nerve stimulation decreases left ventricular contractility in vivo in the human and pig heart.

1. Studies of the effect of vagus nerve stimulation on ventricular myocardial function in mammals are limited, particularly in the human. 2. The present study was designed to determine the effect of direct electrical stimulation of the left vagus nerve on left ventricular contractile state in hearts paced at 10 % above the natural rate, in anaesthetised pigs and anaesthetised human subjects undergoing open chest surgery for coronary artery bypass grafting. 3. Contractility of the left ventricle was determined from a series of pressure-volume loops obtained from a combined pressure and conductance (volume) catheter placed in the left ventricle. From the measurements a regression slope of the end-systolic pressure-volume relationship was determined to give end-systolic elastance (Ees), a load-independent measure of contractility. 4. In six anaesthetised open chest pigs, stimulation of the peripheral cut end of the left cervical vagus nerve induced a significant decrease in Ees of 26 +/- 14 %. 5. In nine patients electrical stimulation of the left thoracic vagus nerve close to its cardiac branch resulted in a significant drop in Ees of 38 +/- 16 %. 6. The effects of vagal stimulation were blocked by the muscarinic antagonist glycopyrronium (5 mg kg(-1)). 7. Administration of the beta-adrenoreceptor antagonist esmolol (1 mg kg(-1)) also attenuated the effect of vagal stimulation, indicating a degree of interaction of vagal and sympathetic influences on contractility. 8. These studies show that in the human and pig heart the left vagus nerve can profoundly decrease the inotropic state of the left ventricular myocardium independent of its bradycardic effect.

Thoracic vagus section distal to the recurrent laryngeal nerve reduces substance. P-immunoreactive innervation in the rat bronchial tree.

The vagal nerve trunk in the mediastinum of mammals divides into two main branches, the thoracic vagus nerve and the recurrent laryngeal nerve, in which the sensory nerve axons are largely involved in neurogenic inflammation in the tracheobronchial airways. A previous study demonstrated that cutting the right-side thoracic vagus nerve but not the recurrent laryngeal nerve inhibited capsaicin-induced neurogenic inflammation in the right bronchial tree of the rat. The effect of left thoracic vagus nerve section is still not known. The main purpose of the present study was to investigate the effect of sectioning the right or left thoracic vagus nerve on the innervation density of substance P-immunoreactive axons in bilateral bronchial trees. Following nerve degeneration, the whole mounts of airway tissues were processed with substance P immunohistochemistry. Denervation of either thoracic vagus nerve reduced the innervation density of axons by 38-71% in different parts of the ipsilateral bronchial tree. The effect of right recurrent laryngeal nerve section was less specific; the innervation density was reduced by 21-39% in the trachea and bronchi of both sides. Capsaicin-induced neurogenic plasma leakage was decreased in the left mainstem bronchus and lobar bronchi after left thoracic vagus nerve section. It is concluded that the thoracic vagus nerve largely contributed to the sensory innervation in the ipsilateral bronchial airways and modulated their functions.

Vagal innervation of the gastrointestinal tract arises from dorsal motor nucleus while that of the heart largely from nucleus ambiguus in the cat

The origin of medullary cells that form the cardiac vagal branch and the vagal branches in the lower thorax innervating the gastrointestinal (GI) tract was studied using horseradish peroxidase (HRP), a retrograde transport tracer in the cat. The distributions of parasympathetic postganglionic neurons of the heart were studied with acetylcholinesterase histochemistry. Intracardiac ganglionic neurons were found mainly in the connective tissue surrounding the base of the pulmonary arteries and in an area in and dorsal to the interatrial septum. Following injection of HRP into the subepicardum where most of the cardiac postganglionic neurons reside, 91% of the labelled neurons were found bilaterally distributed in the nucleus ambiguus (NA). A small population of labelled neurons was found in the dorsal motor nucleus of the vagus (DMV) and an intermediate zone (IZ) between the two nuclei. When HRP was injected into the left or right cardiopulmonary vagus branch, labelled neurons were found exclusively in the ipsilateral NA, DMV and IZ with a predominance in the NA. In the thorax, after they course around the heart, the left and right thoracic vagus nerves divides into a left and a right branch, respectively. The left branch of the left thoracic vagus joins the left branch of the right thoracic vagus to form the anterior vagus nerve at 3 cm above the diaphragm. The right branch of the right thoracic vagus nerve joins the right branch of the left thoracic vagus to form the posterior vagus nerve. After application of HRP into the right or the left branch of the left thoracic vagus, HRP labelled cells were found in the left DMV. Similarly, after application of HRP into the left or the right branch of the right thoracic vagus, labelled cells were found in the right DMV. On the other hand, when HRP was injected into the anterior vagus, labelled neurons were found bilaterally in the DMV. This suggests that all rostral branches of the thoracic vagus have their origin in the ipsilateral DMV, and intermixing occurs only at the caudal level near the diaphragm. Findings of the present experiments suggest that parasympathetic preganglionic neurons innervating the GI tract are located exclusively in the DMV while those of the heart are located mainly in the NA. Within the DMV, GI vagal neurons were found medially from the level 0–2.5 mm rostral to the obex. In contrast, cardiac vagal neurons were found in the lateral edge of the DMV at the level 0–1 mm rostral to the obex.

Vagal, sympathetic and somatic sensory inputs to upper cervical (C1-C3) spinothalamic tract neurons in monkeys.

1. Myocardial ischemia activates vagal and sympathetic cardiac afferent fibers. The purpose of this study was to determine a neuro physiological basis for cardiac pain referred to C1-C3 somatic dermatomes. We hypothesized that afferent fibers traveling in vagal or sympathetic nerves transmit nociceptive information to C1-C3 spinothalamic tract (STT) neurons. 2. Electrical stimulation of the left stellate ganglion to excite cardiopulmonary sympathetic afferent fibers increased extracellular activity of 44 of 77 C1-C3 STT neurons examined in 33 anesthetized male monkeys (Macaca fascicularis); responses increased as stimulus strength increased. Additionally, this stimulus inhibited 5 cells, increased/decreased activity of 2 cells, and did not affect 26 cells. 3. Electrical stimulation of the left (ipsilateral) thoracic vagus nerve excited 41 of 78 C1-C3 STT neurons, inhibited 4 neurons, increased/decreased activity of 2 neurons, and did not affect 31 neurons. Responses increased with increasing stimulus strength Contralateral vagal stimulation excited 7 of 39 cells tested, inhibited 4 cells and did not affect 28 cells. 4. Effects of stimulating one or more vagal branches were examined on 22 C1-C3 STT neurons excited by input from left thoracic vagus nerve. Stimulation of the cardiac branch excited 11 of 16 cells tested; stimulation of the recurrent laryngeal nerve excited 11 of 18 cells; stimulation of vagal fibers just rostral to the diaphragm excited 8 of 19 cells. 5. Excitatory somatic receptive fields ranged from small ipsilateral fields to large, sometimes bilateral or noncontinuous fields. Many fields included the ipsilateral neck and/or inferior jaw. Thirty-nine of 74 neurons examined were wide dynamic range (WDR), 21 were high threshold (HT), 6 were low threshold (LT), and 8 did not respond to brushing or noxious pinching of somatic tissues. Most (38 of 39) WDR cells responded to stimulation of the stellate ganglion or vagal fibers, as did 18 of 21 HT cells, 3 of 6 LT cells, and 2 of 8 cells unresponsive to brush or pinch stimuli. 6. Results of this study supported the concept that vagal and/ or sympathetic afferent activation of C1-C3 STT neurons might provide a neural mechanism for referred pain that originates in the heart or other visceral organs but is perceived in the neck and jaw region. Additionally, C1-C3 STT neurons processed sensory information from widespread regions of the body.

T2-T5 spinothalamic neurons projecting to medial thalamus with viscerosomatic input.

Spinothalamic tract neurons projecting to medial thalamus (M-STT cells), ventral posterior lateral nucleus (VPL) of the thalamus (L-STT cells), or both thalamic regions (LM-STT cells) were studied in 19 monkeys anesthetized with alpha-chloralose. Twenty-seven M-STT cells were antidromically activated from nucleus centralis lateralis, nucleus centrum medianum, or the medial dorsal nucleus. Stimulation of VPL elicited antidromic responses from 22 cells and 13 cells were activated from both VPL and medial thalamus. Antidromic conduction velocities of M-STT cells were significantly slower than those of L-STT or LM-STT cells. M-STT cells were located in laminae I, IV, V, and VII with greater numbers found in the deepest laminae. L-STT cells were located mostly in lamina IV, whereas most LM-STT cells were found in lamina V. Twenty-four of 27 M-STT cells, all L-STT cells, and all LM-STT cells received input from both cardiopulmonary sympathetic and somatic afferent fibers. WDR cells were most common among the L-STT and LM-STT groups, whereas HT cells were the most common class in the M-STT cell group. Excitatory receptive fields of M-STT cells were large, and often bilateral. Receptive fields of L-STT cells were simple and never bilateral. Receptive fields of LM-STT cells could be similar to M-STT or L-STT cells. Thirty-three percent of the M-STT cells, 37% of the L-STT cells, and 62% of the LM-STT cells had inhibitory receptive fields. Inhibition was elicited most often by a noxious pinch of the hindlimbs. Sixteen of 23 (70%) M-STT cells received C-fiber cardiopulmonary sympathetic input in addition to A-delta-fiber input. The other 7 cells received only A-delta-fiber input. Only 45% of the L-STT cells and 38% of the LM-STT cells received both A-delta- and C-fiber inputs. The maximum number of spikes elicited by A-delta-input was related to segmental locations for L-STT cells with greatest responses in T2 and lesser responses in more caudal segments; however, no such trend was apparent for M-STT cells or for responses to C-fiber input for either group. Electrical stimulation of the left thoracic vagus nerve inhibited 7 of 18 M-STT cells, 10 of 16 L-STT cells, and 6 of 12 LM-STT cells. These results are the first description of visceral input to cells projecting to medial thalamus.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of oesophageal and intestinal receptors in the control of gastric motility

The aim of this work was to characterize the discharge pattern of vagal efferent fibers supplying the stomach, and the modifications of this pattern induced by stimulation of oesophageal or intestinal receptors. The experiments were performed on dogs in which the central end of the left thoracic vagus had been sutured to the peripheral end of the left phrenic nerve. In such preparations, the activity of the motor units of the reinnervated left hemidiaphragm indicated the activity of vagal efferent fibers. After the left hemidiaphragm had been transformed into subcutaneous muscle, it was possible to study, using electromyography, in the conscious dog, the discharge of efferent vagal fibers which originally supplied the stomach. All the gastric vagal efferent fibers presented a spontaneous discharge with a very low frequency (0.1 Hz < f < 5 Hz). The firing of some fibers was increased each time the gastric motility was enhanced: these fibers were considered to be excitatory fibers. In contrast, other fibers exhibited an opposite discharge pattern and they were considered to be inhibitory fibers. Among all the gastric fibers whose activity was recorded in this study, some of them presented a modification of discharge during the receptive relaxation of the proximal stomach produced by an oesophageal distension. The discharge of excitatory fibers was suppressed while that of the inhibitory fibers was markedly increased. Taking into account these modifications of discharge, parallel to the relaxation of the proximal stomach, it was assumed that these fibers originally supplied the gastric fundus. Other fibers whose discharge remained unchanged during receptive relaxation were supposed to supply the distal stomach, i.e. the gastric antrum. During gastric emptying, when a small inflated baloon, propelled by gastric peristalsis entered the duodenum, the discharge frequency of all the excitatory fibers was decreased whereas that of the inhibitory fibers was enhanced. Similar variations of discharge were observed during the enterogastric inhibitory reflex, caused by an intraduodenal infusion of hydrochloric acid.

Greater splanchnic excitation of primate T1-T5 spinothalamic neurons.

Effects of electrical stimulation of the left greater splanchnic nerve (SPL) on T1-T5 spinothalamic (STT) neurons were determined. Eighty-five STT neurons were studied in 36 anesthetized monkeys (Macaca fascicularis). All neurons were excited by manipulation of their somatic receptive fields and by electrical stimulation of cardiopulmonary (CP) sympathetic afferent fibers. SPL stimulation excited 63 (74%) STT neurons. There was an increasing percentage of cells with SPL input at more caudal segments and in deeper laminae. Both SPL and CP sympathetic stimulation elicited early or both early and late responses. Latencies to cell activation were usually shorter for CP sympathetic stimulation than for SPL stimulation (5.4 +/- 0.8 versus 11.3 +/- 2.0 ms for early responses and 44.2 +/- 4.2 versus 111.0 +/- 6.6 ms for late responses). The maximum number of spikes per SPL or CP sympathetic stimulus was determined. In the T2 and T3 segments, early responses to CP sympathetic stimulation were significantly greater. However, at more caudal segments, responses to CP sympathetic input decreased while responses to SPL input increased until at T4 there was no difference in the two responses. In T5, responses to SPL input were greater. No differences in the magnitudes of late responses were observed in any of the segments. The response of six cells to SPL stimulation was inhibited by a train of conditioning stimuli applied to the left thoracic vagus nerve. Maximum inhibition occurred at a CT interval of 50 ms and test responses were significantly reduced at CT intervals as great as 200 ms. Bilateral vagotomy eliminated the inhibitory effect. Cutting the left sympathetic chain between the T5 and T6 rami communicantes eliminated 27% of the response to SPL stimulation. More caudal cuts reduced the response further until 71% of the response was abolished by a cut between T8 and T9. Lesions in the dorsolateral column of the spinal cord had little effect on the responses, while lesions of the lateral and ventrolateral columns reduced or abolished the responses. We conclude that SPL stimulation excites T1-T5 STT neurons by way of extraspinal and intraspinal pathways. SPL information is integrated with information from a variety of other visceral and somatic sources. SPL input to cells with somatic fields in the chest region may explain the clinical phenomenon of chest pain associated with abdominal disorders.

Vagal afferent inhibition of spinothalamic cell responses to sympathetic afferents and bradykinin in the monkey.

Effects of stimulating the left thoracic vagus nerve on the responses of spinothalamic neurons to electrical stimulation of cardiopulmonary sympathetic afferent fibers and to intracardiac injections of bradykinin were determined. Experiments were performed on 39 monkeys (Macaca fascicularis) tranquilized with ketamine and anesthetized with alpha-chloralose. The 30 spinothalamic cells studied had the following characteristics. They were excited by manipulation of their somatic receptive fields, were excited by electrical stimulation of cardiopulmonary sympathetic afferent fibers, and exhibited viscerosomatic convergence. Responses of 15 of 19 cells to sympathetic afferent test stimuli were inhibited by conditioning stimuli applied to left thoracic vagus nerve. A conditioning-test interval of 40-50 msec resulted in maximal inhibition of responses to both A delta and C fiber sympathetic afferents. A long time course of inhibition was present to at least a conditioning-test interval of 200 msec. Left thoracic vagus nerve stimulation inhibited 14 of 14 cells responding to intracardiac injection of bradykinin. Entrainment of activity of five cells to the cardiac cycle occurred in response to bradykinin. In each case, left thoracic vagus nerve stimulation, in addition to reducing frequency of cell discharge, disrupted the cardiac related pattern of cell activity. Bilateral cervical vagotomy abolished all inhibitory effects of left thoracic vagus nerve stimulation. These results demonstrate that vagal afferents may participate in processing of information related to cardiac pain.

Effects of individual cardiac nerve stimulation on atrioventricular conduction

This study investigated the effects of individual canine cardiac nerve stimulation on atrioventricular conductions as measured by His bundle electrograms. A-H and H-V intervals were measured before and during stimulation of each nerve in paced hearts (200 beats/min) and before and after blocking doses of either atropine or propranolol. Increases in A-H or H-V intervals were evidence of parasympathetic innervation; decreases in intervals were evidence of sympathetic innervation. Separation by autonomic composition produced 3 categories: sympathetic, parasympathetic, and mixed input to the atrioventricular junction. The sympathetic nerves were the left and right ansae subclavia, the ventrolateral cardiac nerve, and the right stellate cardiac nerve. The parasympathetic nerve was the right thoracic vagus, and the mixed nerves were the left thoracic vagus, and the innominate, ventromedial, craniovagal, caudovagal, and right recurrent cardiac nerves. The cardiac nerves eliciting a major response were the left and right ansae subclavia, the ventrolateral, right recurrent, craniovagal, and caudovagal cardiac nerves, and the left and right thoracic vagi. In theory, the nerves of the right side, because of their innervation of both sinoatrial and atrioventricular nodes, may be expected to elicit a balanced heart rate-atrioventricular conduction response when stimulated, thus matching atrial and ventricular rates. On the other hand, stimulation of the ventrolateral cardiac nerve regularly produces dysrhythmia, due to increased automaticity at the atrioventricular junction. Production of such arrhythmias indicates the possible implication of imbalanced autonomic activity in arrhythmogenesis. Three cardiac nerves produced little or no effect on atrioventricular conduction. These were the innominate, ventromedial, and right stellate cardiac nerves. Because of its limited distribution and marked sinus rate effects, the right stellate cardiac nerve can be considered almost a purely positive chronotropic nerve. Its possible role in heart rate-atrioventricular conduction mismatching has not been delineated but, because of its nearly exclusive action at the sinoatrial node, may be of considerable importance.

Functional significance of thoracic vagal branches in the chicken

One minute electrical stimulation was used to excite the right and left cervical vagi as well as specific points on, or branches of, the left thoracic vagus. Respiratory, heart rate and blood pressure responses were observed with the nerves intact and cut. Stimulation of either intact cervical vagus produced apnea, bradycardia and blood pressure depression. Stimulation of the cut ends after nerve section demonstrated that the heart rate and blood pressure effects were efferent and the respiratory change was afferent. No responses were observed due to stimulation of the vagus caudal to the lungs. Stimulation of cardiac branches reduced heart rate and blood pressure but did not produce significant respiratory effects. Middle and anterior pulmonary branches were found to contribute only to respiratory changes through afferent nerves. Sudden, sustained reduction of CO 2 in the airways produced immediate, sustained apnea. The data suggest that CO 2 sensitive thoracic receptors important in regulation of respiration are confined primarily to the lungs and that these receptors play no direct role in cardiovascular function.

Mechanical stimuli exciting type A atrial vagal receptors in the cat.

The activity of type A right atrial vagal receptors was recorded from the right cervical vagus in cats anesthetized with sodium pentobarbital, immobilized with gallamine, and with their chests open. Nerve impulses initiated by receptor activation were recorded simultaneously with instantaneous right atrial pressure and dimensional changes under various hemodynamic conditions. Atrial volume changes induced by infusion of saline, bleeding, and occlusion of the inferior vena cava did not alter consistently the systolic activity of the receptors. Electrical stimulation of the right stellate ganglion significantly increased the frequency of discharge during systole, whereas electrical stimulation of the left thoracic vagus significantly reduced the frequency of discharge. These inotropic interventions produced similar effects when the heart was paced at a fixed rate. Pacing the right atrial appendage increased the systolic discharge of the receptors only when at high rates the atrium contracted against closed atrioventricular valves. To investigate the influence of tonic efferent sympathetic activity on spontaneous receptor discharge, three receptors were studied before and after bilateral surgical stellectomy, and in cats with their chest closed three receptors were studied before and after infusion of propranolol. Both of these interventions markedly reduced the systolic activity. In addition to having effects on systolic activity, injection of saline, vagal stimulation, and sympathetic "denervation" always activated the receptors during filling. Our results indicate that: (1) the systolic discharge of type A receptors is a function of the active tension developed by atrial muscle during contraction; and (2) the pattern of discharge of the receptors during the atrial cycle depends on both the degree of atrial distention and the state and extent of contraction.