Protective effect of electrical stimulation of the vagus nerve in lipopolysaccharide­induced acute lung injury in rats.

The present study investigated the role of electrical stimulation of the vagus nerve in the acute lung injury (ALI) inflammatory response induced by lipopolysaccharide (LPS) in rats. A rat model of ALI was established using LPS and by connecting an electrode to the left vagus nerve proximal to the heart in order to provide continuous electrical stimulation (1 mA; 1 msec; 10 Hz). After 120 min, the rat lung tissue was stained with hematoxylin and eosin and the expression of inflammatory factors was evaluated by reverse transcription­quantitative PCR and western blot analysis. The change in apoptosis rate in cells from bronchoalveolar lavage fluid (BALF) was analyzed using flow cytometry. The results of the present study demonstrated that inflammatory cell infiltration, alveolar wall and interstitial thickening, and lung hyperemia in rats with LPS­induced ALI were decreased following electrical stimulation of the vagus nerve. Electrical stimulation inhibited the expression levels of IL­1, IL­6, IL­10, IL-8 and TNF­α at both the mRNA and protein levels and decreased early and late apoptosis rates in inflammatory cells from BALF. The results indicated that vagus nerve stimulation can reverse the inflammatory response in lung injury, thereby exerting a pulmonary protective effect.

Incidence and outcomes of radiation-induced late cranial neuropathy in 10-year survivors of head and neck cancer.

OBJECTIVES: To characterize the late cranial neuropathy among 10-year survivors of head and neck cancer treatment. MATERIALS AND METHODS: We retrospectively evaluated patients treated with curative-intent radiation for HNC between 1990 and 2005 at a single institution with systematic multidisciplinary follow-up ≥ 10 years. New findings of CNP were considered radiation-induced when examination, imaging and/or biopsy did not demonstrate a structural or malignant cause. Cox proportional hazards modeling was used for univariable analysis (UVA) and multivariable analysis (MVA) for time to CNP after completion of radiation. RESULTS: We identified 112 patients with no evidence of disease and follow-up ≥ 10 years (median 12.2). Sixteen (14%) patients developed at least one CNP. The median time to CNP was 7.7 years (range 0.6-10.6 years). Most common was CN XII deficit in eight patients (7%), followed by CN X deficit in seven patients (6%). Others included CN V deficit in three, and CN XI deficit in two. Eight of the thirteen patients with a CN X and/or CN XII deficit required a permanent gastrostomy tube. On UVA, site of primary disease, post-radiation neck dissection, chemotherapy, and radiation dose were significantly associated with increased risk of CNP. CONCLUSION: Iatrogenic CNP may develop years after head and neck cancer treatment and often leads to swallowing dysfunction. Long-term follow up is essential for these patients receiving head and neck radiation.

Suppression of vagal cardiac modulation by blue light in healthy subjects.

BACKGROUND: In the contemporary life environments, our body is increasingly exposed to various sources of colored light, which may affect our physiological functions as non-image-forming effects. We examined the impacts of colored lights on the autonomic functions by the analysis of heart rate variability (HRV). METHODS: A lighting device consisting of four organic light-emitting diode (OLED) modules (55 × 55 mm2) with adjustable red-green-blue color was secured 24 cm above the eyes of subject lying supine in a light-shielded laboratory. Following a 15-min supine rest, electrocardiogram and respiration were measured continuously during 3-min darkness, 6-min colored OLED illumination, and 3-min darkness under paced breathing (15 breath/min). The measurements were repeated at a 45-min interval for red, green, and blue lights with melanopsin-stimulating photon flux density (MSPFD) of 0.00, 0.10, and 0.20 µmol/m2/s, respectively, in 12 healthy subjects (23 ± 2 years, two females). Additionally, the effects of blue lights with 0.20, 0.10, and 0.04 µmol/m2/s MSPFD were examined in four healthy subjects (25-39 years, two females). HRV was analyzed for low-frequency (LF, 0.04-0.15 Hz) and high-frequency (HF, 0.20-0.30 Hz) power and LF-to-HF ratio (LF/HF). RESULTS: Compared to darkness before lighting, HF power decreased (P < 0.001) and LF/HF increased (P = 0.024) during lighting on average of all color lights, whereas HF power showed a greater decrease with blue light than with red and green lights (P < 0.05 for both). The decrease in HF power lasted even during darkness after lighting (P < 0.001). HF power decreased with blue light with 0.20 µmol/m2/s MSPFD (P < 0.001) but not with that with 0.10 or 0.04 µmol/m2/s (P = 0.1 and 0.9, respectively). CONCLUSIONS: Vagal cardiac modulation is suppressed by OLED blue light in healthy subjects most likely through melanopsin-dependent non-image-forming effect.

Dosimetric predictors of radiation-induced acute nausea and vomiting in IMRT for nasopharyngeal cancer.

PURPOSE: We wanted to investigate dosimetric parameters that would predict radiation-induced acute nausea and vomiting in intensity-modulated radiation therapy (IMRT) for undifferentiated carcinoma of the nasopharynx (NPC). METHODS AND MATERIALS: Forty-nine consecutive patients with newly diagnosed NPC were treated with IMRT alone in this prospective study. Patients receiving any form of chemotherapy were excluded. The dorsal vagal complex (DVC) as well as the left and right vestibules (VB-L and VB-R, respectively) were contoured on planning computed tomography images. A structure combining both the VB-L and the VB-R, named VB-T, was also generated. All structures were labeled organs at risk (OAR). A 3-mm three-dimensional margin was added to these structures and labeled DVC+3 mm, VB-L+3 mm, VB-R+3 mm, and VB-T+3 mm to account for physiological body motion and setup error. No weightings were given to these structures during optimization in treatment planning. Dosimetric parameters were recorded from dose-volume histograms. Statistical analysis of parameters' association with nausea and vomiting was performed using univariate and multivariate logistic regression. RESULTS: Six patients (12.2%) reported Grade 1 nausea, and 8 patients (16.3%) reported Grade 2 nausea. Also, 4 patients (8.2%) complained of Grade 1 vomiting, and 4 patients (8.2%) experienced Grade 2 vomiting. No patients developed protracted nausea and vomiting after completion of IMRT. For radiation-induced acute nausea, V40 (percentage volume receiving at least 40Gy) to the VB-T and V40>=80% to the VB-T were predictors, using univariate analysis. On multivariate analysis, V40>=80% to the VB-T was the only predictor. There were no predictors of radiation-induced acute vomiting, as the number of events was too small for analysis. CONCLUSIONS: This is the first study demonstrating that a V40 to the VB-T is predictive of radiation-induced acute nausea. The vestibules should be labeled as sensitive OARs, and weightings should be considered for dose sparing during optimization in the treatment planning of IMRT.

Neurostimulation therapies for treatment resistant depression: a focus on vagus nerve stimulation and deep brain stimulation.

Antidepressant treatments, including pharmacotherapy and psychotherapy, do not result in remission for the majority of patients with major depressive disorder. The high prevalence of treatment resistant depression (TRD) poses a significant issue for patients as well as both societal and economic costs. Due to the limited efficacy of existing therapies in this sub-population, alternative somatic treatments are being explored. Both vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are neurostimulation treatments for TRD. While VNS has Food Drug Administration approval as an adjunctive therapy for MDD, DBS is still in the experimental stages. This article will review the evidence supporting the clinical utility of these therapies.

Effect of brain stem and dorsal vagus complex dosimetry on nausea and vomiting in head and neck intensity-modulated radiation therapy.

Intensity-modulated radiation therapy (IMRT) is becoming the treatment of choice for many head and neck cancer patients. IMRT reduces some toxicities by reducing radiation dose to uninvolved normal tissue near tumor targets; however, other tissues not irradiated using previous 3D techniques may receive clinically significant doses, causing undesirable side effects including nausea and vomiting (NV). Irradiation of the brainstem, and more specifically, the area postrema and dorsal vagal complex (DVC), has been linked to NV. We previously reported preliminary hypothesis-generating dose effects associated with NV in IMRT patients. The goal of this study is to relate brainstem dose to NV symptoms. We retrospectively studied 100 consecutive patients that were treated for oropharyngeal cancer with IMRT. We contoured the brainstem, area postrema, and DVC with the assistance of an expert diagnostic neuroradiologist. We correlated dosimetry for the 3 areas contoured with weekly NV rates during IMRT. NV rates were significantly higher for patients who received concurrent chemotherapy. Post hoc analysis demonstrated that chemoradiation cases exhibited a trend towards the same dose-response relationship with both brainstem mean dose (p = 0.0025) and area postrema mean dose (p = 0.004); however, both failed to meet statistical significance at the p ≤ 0.002 level. Duration of toxicity was also greater for chemoradiation patients, who averaged 3.3 weeks with reported Common Terminology Criteria for Adverse Events (CTC-AE), compared with an average of 2 weeks for definitive RT patients (p = 0.002). For definitive RT cases, no dose-response trend could be ascertained. The mean brainstem dose emerged as a key parameter of interest; however, no one dose parameter (mean/median/EUD) best correlated with NV. This study does not address extraneous factors that would affect NV incidence, including the use of antiemetics, nor chemotherapy dose schedule specifics before and during RT. A prospective study will be required to depict exactly how IMRT dose affects NV.

Treatment strategies for obsessive-compulsive disorder.

IMPORTANCE OF THE FIELD: In the last decades, the treatment of obsessive-compulsive disorder (OCD) has improved significantly with the introduction into the clinical practice of the selective serotonin reuptake inhibitors (SSRIs): this has led to a renewed interest in this condition and development of appropriate therapeutic strategies, including non-pharmacological techniques. AREAS COVERED IN THIS REVIEW: The aim of this paper is to present a comprehensive and critical review of pharmacological and non-pharmacological treatments usually adopted in the management of OCD. MEDLINE and PubMed (1980 - 2009) databases were searched for English-language articles by using the following keywords: OCD, clomipramine, SSRIs, resistance, predictor of response, cognitive-behavioral therapy, exposure and response prevention, repetitive transcranial magnetic stimulation, deep brain stimulation, neurosurgery, electroconvulsive therapy. WHAT THE READER WILL GAIN: The reader will gain an exhaustive review of the advantages and disadvantages of the treatments usually adopted in OCD, with a special focus on resistance and clinical features that can be used as predictors of response. TAKE HOME MESSAGE: Obsessive-compulsive disorder is a common psychiatric condition that can be adequately managed with the currently available therapeutic options. Although a certain percentage of patients do not achieve complete clinical remission, improvement of some of their core symptoms permits them to live more satisfying lives and to reach a better social adjustment.

Vagal paraganglioma of the neck: a case report.

Vagal paragangliomas are rare in the head and neck. Complementary use of computed tomography and magnetic resonance imaging can facilitate the diagnosis and help determine the best management approach. Most paragangliomas should be treated with surgery. We report a case of vagal paraganglioma of the neck in a 50-year-old man. The patient was treated with superficial parotidectomy via a transcervical approach. No postoperative morbidity was noted, and at 3 years of follow-up, he was free of disease.

N-terminal pro-brain natriuretic peptide (NT-proBNP) release in children with vagus nerve stimulation. A prospective case series.

Brain natriuretic peptide(BNP) and the N-terminal pro-brain natriuretic peptide (NTproBNP)are important cardiac biomarkers secreted by the heart in response to increased ventricular wall stress associated with heart failure. The aim of our case series was to prospectively evaluate the influence of vagus nerve stimulation (VNS) on the release of NTproBNP.Three children with medically refractory epilepsy and scheduled for implantation of the VNS device were included. Pre-implantation,NT-proBNP measurements were taken at two different occasions after seizure-free periods of at least three days. After implantation,NT-proBNP measurements were taken every 2 to 4 weeks, immediately before and immediately after up-regulation of the VNS. After VNS implantation, the pattern of NT-proBNP increase was consistent for all children. In a 12 year-old girl, NT-proBNP concentrations reached a maximum of an almost 10-fold increase. Thereafter, NTproBNP concentrations returned continuously to baseline. In a three year-old boy, NT-proBNP concentrations reached a maximum of an almost 7-fold increase, accompanied by manifestation of side effects(voice alterations, snoring).Thereafter, NT-proBNP concentrations decreased to almost 4-fold those at baseline. In an 8 year-old girl, NT-proBNP concentrations increased slightly without yet reaching a plateau. This case series suggests that NT-proBNP concentrations increase in response to VNS-induced autonomic influences involving endocrinological stress-response mechanisms typically associated with cardiac injury.Especially in patients with pre-existing cardiovascular dysfunction,measurement of NT-proBNP concentrations may help to identify patients with high baseline concentrations and possibly at greater risk for cardiac side effects.

Antiepileptic effect of electroacupuncture vs. vagus nerve stimulation in the rat thalamus.

Our previous study has shown that both electroacupuncture (EA) and vagus nerve stimulation (VNS) can inhibit cortical epileptiform activities induced by pentylenetetrazole (PTZ). The current study compared the effects of EA and VNS on thalamic neuronal responses to PTZ-induced epileptiform activities. Under general anesthesia, extracellular single unit recordings were made from 49 single neurons in the rat ventrobasal (VB) thalamus. The left vagus nerve was stimulated at 30 Hz, 1 or 3 mA for 5 min. For EA, "Dazhui" acupoint (GV14) was stimulated with the same parameters. It was found that (1) the VB thalamic neurons showed epileptiform activities after PTZ injection; (2) VNS and EA could predominantly inhibit the PTZ-induced epileptiform activities in the thalamic neurons. The higher intensity stimulation (3 mA) in either VNS or EA was, however, not associated with a greater inhibition. Our study suggests that both EA and VNS reduce epileptiform activities at the thalamic level, and EA may be an alternative to VNS.

Antiepileptic effects of electroacupuncture vs vagus nerve stimulation on cortical epileptiform activities.

Introduced about two decades ago, vagus nerve stimulation (VNS) therapy has been increasingly used for the treatment of refractory epilepsy recently. This study was set out to compare the effects between VNS and electroacupuncture (EA) on pentylenetetrazole (PTZ) induced epileptiform activities in the rat cerebral cortex. Under general anesthesia, the parietal cortex of the rat (n=20) was exposed to record the cortical epileptiform activities. The left vagus nerve was stimulated at 30 Hz, 1 mA or 3 mA for 5 min. For EA, "Dazhui" acupoint (GV14) was stimulated with a pair of acupuncture needles with the same parameters. The results show that both VNS and EA at either 1 mA or 3 mA could inhibit the PTZ-induced cortical epileptiform activities, and higher stimulation (3 mA) was not associated with a greater inhibition. In the cases that showed inhibitory responses, there were no statistically significant differences between the two modalities, implying that EA could be comparable to VNS in the treatment of epilepsy. Thus, under current experimental settings, the antiepileptic effect induced by electrical stimulation appeared not vagal specific, and EA could be a good alternative to VNS in the management of epilepsy.

Vagus nerve stimulation for epilepsy and depression.

Many patients with epilepsy suffer from persistent seizures despite maximal antiepileptic drug (AED) therapy. Chronic, intermittent vagus nerve stimulation (VNS) has proven to be a safe, effective option for patients suffering from refractory seizures who are not candidates for surgical resection. Although only a small minority of patients will be entirely seizure-free, VNS as an adjunct to medical therapy does appear to provide a significant amount of improvement in quality of life. Reports of antidepressant effects independent of seizure control, along with the use of multiple AEDs in the treatment of depression, has led to the investigation of VNS as a potential adjunctive treatment for major depressive disorder. Both the number of severely depressed patients refractory to available pharmacologic options and the need for repeated treatments and significant side effects associated with electroconvulsive therapy have heightened the interest in VNS for this patient population. Pilot studies of VNS for depression have shown impressive response rates; however, the effect appears to be gradual in onset, as demonstrated by the lack of a favorable response in a short-term, randomized controlled study. Investigation is thus needed to establish the potential role of VNS as an adjunctive treatment for severe depression.

Long-term outcome of vagus nerve stimulation therapy in patients with refractory epilepsy.

We retrospectively assessed the long-term efficacy of vagus nerve stimulation (VNS) therapy in 31 patients with refractory partial and generalized seizures who were not candidates for resective epilepsy surgery. Following implantation of VNS there was significant improvement in seizure frequency at 6 months. Sixteen patients continued to have sustained response to VNS therapy 4 years later. Adverse effects of VNS therapy were transient and tolerable. The majority of the patients did not gain body weight and some of them had significant weight loss. Therefore VNS is safe and effective therapy and has a long-term sustained effect in refractory epilepsy.

Striatal projections of the vagal-responsive region of the thalamic parafascicular nucleus in macaque monkeys.

We recently reported that the thalamic parafascicular nucleus (Pf) in monkeys is strongly activated by vagus nerve afferents. The main forebrain target of Pf is the striatum, but the specific striatal regions receiving visceral input via this pathway are unknown. We examined the projections of this region by injecting anterograde tracers into the vagus evoked potential (VEP) focus in Pf of macaque monkeys. The VEP was strongest lateral and anterior to the habenulointerpeduncular tract, but it was distributed across the entire horizontal extent of the ventral half of Pf. All injections produced labeled terminals in the caudate (Cd), especially the Cd tail and the adjacent ventral posterior Pu. Terminations occurred throughout the Cd head and body but spared the most anterior and dorsolateral parts. Injections in more anterior and lateral portions of Pf produced progressively more terminations in Pu, mainly in the precommissural region and the medial aspect of posterior Pu. Dual injections of different tracers revealed overlapping projections with interdigitated strands of striatal terminations from separate regions of Pf as well as the posteromedial to anterolateral topographic gradient of increasing Pf projections to Pu. An injection in the most anteromedial portion of Pf produced strong labeling in the ventral striatum. Thus, Pf transmits viscerosensory information to the "associative" and "limbic" territories of the striatum. These findings suggest the broad involvement of homeostatic afferent activity in striatal function and perhaps a role for the striatum in autonomic function.

Comparison of corpus callosotomy and vagus nerve stimulation in children with Lennox-Gastaut syndrome.

PURPOSE: To compare the efficacy of corpus callosotomy and vagus nerve stimulation (VNS) for long-term adjunctive therapy in children with Lennox-Gastaut syndrome (LGS). METHOD: Fourteen patients underwent a total corpus callosotomy and 10 patients received VNS implantation. The patients were monitored for more than 12 months after treatment, and seizure rates and complications were retrospectively evaluated. RESULTS: Seizure types among the 24 patients included atonic or tonic seizures with head-drops in 17 patients, generalized tonic seizures in two patients, atypical absence seizures in one patient, generalized tonic-clonic seizures in one patient, and myoclonic seizures in three patients. Of the 14 patients who underwent a corpus callosotomy, nine (64.3%) had a greater than 50% reduction in seizure frequency and five (35.7%) had a greater than 75% reduction. Of the 10 patients who underwent VNS implantation, seven (70.0%) had a greater than 50% reduction in seizure frequency and two (20.0%) had a greater than 75% reduction. There was no significant difference between the two procedures in terms of final efficacy. Complications of corpus callosotomy included aphasia in one patient, ataxia in another, and paresis in a third. Among patients receiving VNS, one patient experienced dyspnea while sleeping and one patient suffered from drooling. These complications were transient and tolerable, and were controlled by simple adjustments of VNS treatment parameters. CONCLUSION: The efficacy and safety of corpus callosotomy and VNS were comparable in children with LGS.

N-desmethylclozapine an M1 receptor agonist enhances nitric oxide's cardiac vagal facilitation in the isolated innervated rat right atrium.

We have previously determined that neuronal nitric oxide (NO) may partly mediate its established cholinergic effect via activation of muscarinic type 1 (M1) receptors located at the preganglionic/postganglionic synapse. In this series of experiments we set out to confirm this finding using an M1 agonist. Experiments were carried out on the isolated vagally innervated right atrium in the presence of atenolol (4 microM). The right vagus was stimulated at 4, 8, 16, 32 Hz; pulse duration 1 ms at 20 V for 20 s and the effect on cardiac interval (ms) assessed. N-desmethylclozapine (100 nM), a potent M1 agonist, enhanced the vagally induced increase in cardiac interval, a lower concentration of 50 nM had no significant effect on cardiac interval. This effect was prevented by pre-treatment of the atria with the neuronal NO synthase inhibitor 1 (2-trifluoromethylphenyl)imidazole (TRIM) at 0.14 mM. The vagal stimulation protocol was repeated in order to rule out a reduction in vagal effectiveness which may have been due to the experimental stimulation protocol used in this study. TRIM (0.14 mM) alone causes a small but significant attenuation of the vagally induced increase in cardiac interval. These results show that agonism of M1 receptors on cardiac vagal preganglionic fibres enhances vagal cardiac effects which can be prevented by a neuronal NO inhibitor.

Dorsomedial hypothalamic nucleus neurons integrate important peripheral feeding-related signals in rats.

Several studies have implicated the dorsomedial hypothalamic nucleus (DMN) in regulation of feeding behavior and body weight, but clear mechanisms by which it controls food intake are not well understood. We report the results of the present study, which showed that the DMN receives important peripheral short- and long-term feeding-related afferent signals, including gastric vagal, glycemia, and cholecystokinin (CCK) inputs, as well as from leptin, an adipostatic signal that forcefully inhibits food intake and increases metabolic rate. Among the 279 DMN neurons recorded, 173 (62.0%) responded to stimulation of gastric vagal nerves. Also, of the 123 DMN neurons responsive to gastric vagal stimulation that were tested with the administration of intravenous glucose, 75 (61.0%) were identified as being glycemia sensitive. Moreover, it is noteworthy that of the 23 DMN neurons that responded to both gastric vagal and intravenous glucose stimulation, most (19 of 23, 82.6%) were sensitive to circulating leptin, and some neurons (n = 7) were also responsive to systemic CCK, suggesting that gastric vagal, glycemic, CCK, and leptin inputs converge on single DMN neurons. Furthermore, synergistic interactions between leptin and glucose on single DMN neurons were observed (n = 6). These results demonstrate that those important peripheral feeding-related gastric vagal, glycemic, CCK and leptin signals not only reach the DMN but also interact on single DMN neurons, suggesting that the DMN may not just function as a relay station, but independently integrate the short-term and long-term feeding-associated information and actively participate in the direct regulation of feeding behavior.

Unmyelinated visceral afferents exhibit frequency dependent action potential broadening while myelinated visceral afferents do not.

Sensory information arising from visceral organ systems is encoded into action potential trains that propagate along afferent fibers to target nuclei in the central nervous system. These information streams range from tight patterns of action potentials that are well synchronized with the sensory transduction event to irregular, patternless discharge with no clear correlation to the sensory input. In general terms these afferent pathways can be divided into unmyelinated and myelinated fiber types. Our laboratory has a long standing interest in the functional differences between these two types of afferents in terms of the preprocessing of sensory information into action potential trains (synchrony, frequency, duration, etc.), the reflexogenic consequences of this sensory input to the central nervous system and the ionic channels that give rise to the electrophysiological properties of these unique cell types. The aim of this study was to determine whether there were any functional differences in the somatic action potential characteristics of unmyelinated and myelinated vagal afferents in response to different rates of sensory nerve stimulation. Our results showed that activity and frequency-dependent widening of the somatic action potential was quite prominent in unmyelinated but not myelinated vagal afferents. Spike broadening often leads to increased influx of Ca(2+) ions that has been associated with a diverse range of modulatory mechanisms both at the cell body and central synaptic terminations (e.g. increased neurotransmitter release.) We conclude that our observations are indicative of fundamentally different mechanisms for neural integration of sensory information arising from unmyelinated and myelinated vagal afferents.

Electrical control of epileptic seizures.

SUMMARY: Epilepsy is among the most common neurologic disorders, yet it is estimated that about one third of patients do not respond favorably to currently available drug treatments and up to 50% experience major side effects of these treatments. Although surgical resection of seizure foci can provide reduction or cessation of seizure incidents, a significant fraction of pharmacologically intractable seizure patients are not considered viable candidates for such procedures. Research advances in applying electrical stimulation as an alternative treatment for intractable epilepsy have been reported. The primary focus of these studies has been the search for optimized stimulation protocols by which to electrically suppress, revert or prevent seizures. In this review, the authors discuss some of the promising results that have been achieved. These results are organized in three broad categories based on how such protocols are generated. They focus on how information of the electrical activity in the brain is incorporated in the control schemes, namely: open loop, semiclosed loop, and closed loop protocols. Benefits, potential promises, and challenges of these different control techniques are discussed.