Vagus Nerve Stimulation Activation Research Articles

Teaching Neuro Images : Obstructive sleep apnea triggered by vagus nerve stimulation

A 47-year-old man with drug-resistant cryptogenic epilepsy, treated with vagus nerve stimulation (VNS), underwent polysomnography (PSG) for suspected obstructive sleep apnea (OSA). A previous PSG study, performed 1 year before VNS, had showed an apnea-hypopnea index (AHI) = 4 events/hour, but the patient reported that the activation of the VNS was associated with increase of apneas witnessed by his bed partner. PSG was consistent with mild OSA; the AHI was 14.0 events/hour. During PSG, the stimulator was active for periods of 30 seconds, generating a peculiar artifact (figure, black arrows), separated by a 3-minute interval. In 67% of the obstructive events (9.5 events/hour), the onset of the event was simultaneous or immediately followed the start of VNS activation, suggesting that VNS might trigger obstructive apneas/hypopneas1,2 (figure, white arrows).

Vagus nerve stimulation activates nucleus of solitary tract neurons via supramedullary pathways.

Vagus nerve stimulation (VNS) treats patients with drug-resistant epilepsy, depression and heart failure, but the mechanisms responsible are uncertain. The mild stimulus intensities used in chronic VNS suggest activation of myelinated primary visceral afferents projecting to the nucleus of the solitary tract (NTS). Here, we monitored the activity of second and higher order NTS neurons in response to peripheral vagal activation using therapeutic VNS criteria. A bipolar stimulating electrode activated the left cervical vagus nerve, and stereotaxically placed single tungsten electrodes recorded unit activity from the left caudomedial NTS of chloralose-anaesthetized rats. High-intensity single electrical stimuli established vagal afferent conduction velocity (myelinated A-type or unmyelinated C-type) as well as synaptic order (second vs. higher order using paired electrical stimuli) for inputs to single NTS neurons. Then, VNS treatment was applied. A mid-collicular knife cut (KC) divided the brainstem from all supramedullary regions to determine their contribution to NTS activity. Our chief findings indicate that the KC reduced basal spontaneous activity of second-order NTS neurons receiving myelinated vagal input by 85%. In these neurons, acute VNS increased activity similarly in Control and KC animals. Interestingly, the KC interrupted VNS activation of higher order NTS neurons and second-order NTS neurons receiving unmyelinated vagal input, indicating that supramedullary descending projections to NTS are needed to amplify the peripheral neuronal signal from VNS. The present study begins to define the pathways activated during VNS and will help to better identify the central nervous system contributions to the therapeutic benefits of VNS therapy. KEY POINTS: Vagus nerve stimulation is routinely used in the clinic to treat epilepsy and depression, despite our uncertainty about how this treatment works. For this study, the connections between the nucleus of the solitary tract (NTS) and the higher brain regions were severed to learn more about their contribution to activity of these neurons during stimulation. Severing these brain connections reduced baseline activity as well as reducing stimulation-induced activation for NTS neurons receiving myelinated vagal input. Higher brain regions play a significant role in maintaining both normal activity in NTS and indirect mechanisms of enhancing NTS neuronal activity during vagus nerve stimulation.

Vocal Outcomes in Vagus Nerve Stimulation: A Laryngeal Pattern-Based Objective Analysis

The aim of our study is to evaluate objective and subjective vocal outcomes in patients undergoing vagus nerve stimulation (VNS) therapy for drug-resistant epilepsy and to assess the vocal outcome in the known laryngeal dysmotility patterns induced by VNS. We enrolled 16 adult patients without cognitive impairment who had undergone VNS implant for drug-resistant epilepsy at least 1 year prior. They were evaluated by flexible fibreoptic laryngeal examination and Voice Handicap Index questionnaire administration; acoustic and perceptual voice analysis was performed both at rest and during VNS activation. All recruited patients were admitted to the study. The VNS implant systematically determined laryngeal motility alterations, which were in turn mirrored by perceptual, subjective, and/or acoustic analysis voice alterations in all patients. Patients with intact vocal fold function at rest performed worse during acoustic voice analysis in terms of jitter during VNS activation and shimmer at rest when compared to other laryngeal patterns (P= 0.027 and P=0.034, respectively, Kruskal-Wallis test). Furthermore, VNS activation determined an overall worsening of the perceptual and acoustically analysed voice quality: the grade of hoarseness, instability and breathiness parameters of the GRBASI (grade, roughness, breathiness, asthenia, strain, instability) scale and the jitter, shimmer and noise-to-harmonic ratio of the acoustic analysis worsened significantly during VNS activation (P=0.001, P=0.021, P=0.012, P < .001, P=00.002, P=0.039, respectively, Wilcoxon test). According to our results, the VNS implant determines a significantly impaired vocal outcome that has a surprisingly mild impact on Voice Handicap Index scores. Such impairment is significantly greater in patients with intact vocal fold function at rest.

Chaos or Randomness? Effect of Vagus Nerve Stimulation During Sleep on Heart-Rate Variability

Loss of complexity and chaos of heart rate variability (HRV) of an individual increases the risk of mortality from cardiovascular diseases. Abnormalities in HRV associated with intractable epilepsy may even lead to “sudden death in epilepsy” (SUDEP). By activating the parasympathetic division of the autonomic nervous system, Vagus Nerve Stimulation (VNS) has the potential to restore the natural chaotic behavior of the heart which can be measured by the increase in complexity of HRV as indicated by complexity measures such as Effort-To-Compress (ETC) and Lempel-Ziv Complexity (LZC). In this study, we formulate and test two hypothesis – (A) chaotic time series exhibit lower temporal correlation of complexity measures such as LZ and ETC than uniformly random time series, and (B) Vagus Nerve Stimulation (VNS ON) results in chaotic cardiovascular dynamics. Hypothesis-A is verified by a simulated study on chaotic time series from the Logistic map where we see a clear decrease in temporal correlation between ETC and LZC values as the degree of chaos increases. Hypothesis-B is supported by an experimental study on a VNS implanted patient and not implanted controls. A temporal correlation analysis between complexity measures (ETC and LZC) on HRV data samples shows that VNS during sleep increases chaotic behavior in contrast to lack of VNS and in control subjects. Surrogate analysis further confirmed that VNS activation led to deterministic chaos and not stochastic randomness. Our approach proposes a clear methodology to determine the efficacy of VNS intervention in restoring the chaoticity of cardiovascular dynamics.

The vagal nerve stimulation outcome, and laryngeal effect: Otolaryngologists roles and perspective

IntroductionEpilepsy is one of the most common neurologic disorders. Vagus nerve stimulation (VNS), first investigated in 1938 and subsequently studied as a potential therapy for epilepsy. The FDA approved the use of VNS in 1997 as an adjunctive non-pharmacologic symptomatic treatment option for refractory epilepsy for adults and adolescents over 12years.VNS can cause laryngeal and voice side effects that can be managed by otolaryngologists safely and effectively. ObjectivesThis study is to review the outcomes of vagal nerve stimulator (VNS) implantation in terms of the surgical procedures, complications, seizure frequency, and the clinical effect on larynx and vocal folds motion. MethodsSeries of thirty consecutive patients who had VNS implantation between 2007 and 2014 were recruited. Seizure-frequency outcome, surgical complications and device adverse effects of VNS were retrospectively reviewed. Additional evaluation included use of the Voice Handicap Index and Maximum Phonation Time (MPT) were conducted before and after the implantation.Videolaryngoscopy was used to evaluate the vocal fold mobility before and after the VNS implantation. ResultsSeizure frequency reduction over a minimum of 2years of follow up demonstrated: 100% in seizure frequency reduction in 1 patient, drastic reduction in seizure frequency (70–90%) in 9 patients, a good reduction in terms of seizure frequency (50%) in 8 patients, a 30% reduction in 5 patients, no response in 6 patients, and 1 patient had increased frequency.The most commonly reported adverse effects after VNS activation were coughing and voice changes with pitch breaks, as well as mild intermittent shortness of breath in 33% of patients. For those patients secondary supraglottic muscle tension and hyper function with reduced left vocal fold mobility were noticed on videolaryngoscopy, though none had aspiration problems.Surgical complications included a wound dehiscence in one patient (3%) which was surgically managed, minor intra-operative bleeding 3%; a superficial wound infection in one patient (3%) which was treated conservatively, none of the complications necessitated VNS removal. ConclusionsVNS appears to be an effective non-pharmacologic adjuvant therapy in patients with medically refractory seizures. With the favorable adverse-effect profile previously described, VNS is generally well tolerated and of a great benefit to such patients.Laryngeal side effects, of which hoarseness being of the greatest repetition, are the most common after the VNS implantation. VNS can affect the voice and reduced vocal cord motion on the implantation side with secondary supraglottic muscle tension.Otolaryngologists are not only capable of performing VNS implantation, but can also manage surgical complications, assess laryngeal side effects and treat them as needed.

The role of laryngeal electromyography in vagus nerve stimulation-related vocal fold dysmotility.

Vagus nerve stimulation (VNS) is a useful tool for drug-resistant epilepsy, but it induces known laryngeal side effects, with a significant role on patients' quality of life. VNS patients may show persistent left vocal fold (LVF) palsy at rest and/or recurrent LVF adduction during stimulation. This study aims at electromyographically evaluating laryngeal muscles abnormalities in VNS patients. We compared endoscopic laryngeal evaluation data in six VNS patients with laryngeal muscle electromyography (LMEMG) carried out on the thyroarytenoid, cricothyroid, posterior cricoarytenoid, and cricopharyngeal muscles. Endoscopy showed LVF palsy at rest in 3/6 patients in whom LMEMG documented a tonic spastic activity with reduced phasic modulation. In four out of six patients with recurrent LVF adduction during VNS activation, LMEMG showed a compound muscle action potential persisting for the whole stimulation. This is the first LMEMG report of VNS-induced motor unit activation via recurrent laryngeal nerve and upper laryngeal nerve stimulation. LMEMG data were could, therefore, be considered consistent with the endoscopic laryngeal examination in all patient.

Vagus nerve stimulation and late-onset bradycardia and asystole: Case report

Vagus nerve stimulation (VNS) therapy is approved in the United States by the FDA in 1997 for medically refractory partial epilepsy in patients of ages 12 years and above. The most common stimulation-associated side effects are voice alteration, hoarseness, throat and neck pain, headache, cough, and dyspnea. Four patients with VNS had late-onset bradycardia and asystole, attributed to VNS stimulation. Their ages were 13, 17, 47, and 55. Cardiac symptoms were noted after 2.33–9 years postimplantation [1–4]. Three cases had symptoms correlated with stimulation, monitored by electrocardiogram [1,2,4]. This new case report highlights cardiac syncope with very similar clinical presentation as previous four cases, and raises the concern for cardiac symptoms, even many years after VNS implantation.

Pretreatment cerebral metabolic activity correlates with antidepressant efficacy of vagus nerve stimulation in treatment-resistant major depression: A potential marker for response?

Pretreatment brain activity in major depressive disorder correlates with response to antidepressant therapies, including pharmacotherapies and transcranial magnetic stimulation. The purpose of this trial was to examine whether pretreatment regional metabolic activity in selected regions of interest (ROIs) predicts antidepressant response following 12 months of vagus nerve stimulation (VNS) in 15 patients with treatment-resistant major depression (TRMD). Fluorodeoxyglucose positron emission tomography (FDG PET) was used to assess regional mean relative cerebral metabolic rate for glucose (CMRGlu) in four ROIs (anterior insular, orbitofrontal, anterior cingulate, and dorsolateral prefrontal cortices) at baseline (prior to VNS activation). Depression severity was assessed at baseline and after 12 months of VNS using the Hamilton Depression Rating Scale (HDRS), with response defined as ≥ 50% reduction in HDRS from baseline. Baseline CMRGlu in the anterior insular cortex differentiated VNS responders (n=11) from nonresponders (n=4) and correlated with HDRS change (r=.64, p=.01). In a regression analysis, lower anterior insular cortex CMRGlu (p=.004) and higher orbitofrontal cortex CMRGlu (p=.047) together predicted HDRS change (R(2)=.58, p=.005). In a whole brain, voxel-wise analysis, baseline CMRGlu in the right anterior insular cortex correlated with HDRS change (r=.78, p=.001). Sample size was small, limiting statistical power; patients remained on their psychiatric medications; study was open-label and uncontrolled. This preliminary study suggests that pretreatment regional CMRGlu may be useful in predicting response to VNS in TRMD patients.

Effectiveness and Safety of Vagus Nerve Stimulation for Severe Treatment-Resistant Major Depression in Clinical Practice After FDA Approval

To describe the outcomes of a consecutive series of depressed patients treated with vagus nerve stimulation (VNS) following US Food and Drug Administration (FDA) approval of this intervention. We implanted a VNS device in 15 consecutive outpatients with treatment-resistant major depressive episodes, including 10 with major depressive disorder and 5 with bipolar disorder (DSM-IV criteria), between November 2005 and August 2006. Existing antidepressant treatment remained fixed as far as clinically possible. The primary outcome was change from baseline in the Beck Depression Inventory (BDI) score. Outcomes were assessed at 6 and 12 months postimplant and compared to those of the VNS pivotal efficacy trial that led to FDA approval of VNS. The BDI score decreased significantly compared to baseline at 6 months (P < .05) and 12 months (P < .01), from a mean of 37.8 (SD = 7.8) before VNS activation to a mean of 24.6 (SD = 11.4) at 12 months. By 1 year, 28.6% (n = 4) of the sample responded to VNS and 7.1% (n = 1) remitted according to the BDI. Secondary outcomes on the Hamilton Depression Rating Scale 24-Item showed similar improvement at 1 year, with a 43% response rate (n = 6) and 14.3% remission rate (n = 2). No obvious predictors of response were detected. Side effects of VNS included hoarseness (73%), dyspnea (47%), nausea (40%), pain (33%), and anxiety (20%); no patient terminated treatment due to intolerable side effects. We found that a substantial minority of patients with extremely difficult-to-treat depressive disorders benefited from VNS in an ambulatory clinical practice, with outcomes comparable to those observed in previous VNS efficacy studies and with a similar side effect profile.

Vagus Nerve Stimulation, Sleep Apnea, and CPAP Titration

Epilepsy and obstructive sleep apnea (OSA) are two relatively common disorders known to coexist and potentially exacerbate each other. Vagus nerve stimulation (VNS) is a currently used, adjunctive treatment for partial epilepsy and is generally well tolerated with few associated side effects. Some of the more common side effects include hoarseness of voice, laryngeal irritation and cough, especially after VNS current increases and the first few weeks of treatment. VNS therapy also affects respiration during sleep and has been shown to worsen preexisting obstructive sleep apnea/hypopnea syndrome (OSAHS) by increasing the number of apneas and hypopneas. Consistent sleep related decreases in airflow and effort coinciding with VNS activation have been documented, with apneas and hypopneas found to be more frequent during VNS activation than during nonactivation. VNS may also interfere with effective CPAP titration. The purpose of this case study was to examine the effects of VNS cycling on CPAP titration for OSA in a patient with medically intractable epilepsy. We found that adequate CPAP titration could not be achieved in the presence of the patient's standard VNS on/off cycling mode. However, when the patient was restudied with his VNS device turned off, a nasal CPAP pressure of 13 cm H2O resulted in effective treatment of his severe OSAHS. We suggest that polysomnography before VNS implantation should be considered in order to identify patients with OSA.

Increase in 20–50 Hz (gamma frequencies) power spectrum and synchronization after chronic vagal nerve stimulation

Objective Though vagus nerve stimulation (VNS) is an important option in pharmacoresistant epilepsy, its mechanism of action remains unclear. The observation that VNS desynchronised the EEG activity in animals suggested that this mechanism could be involved in VNS antiepileptic effects in humans. Indeed VNS decreases spiking bursts, whereas its effects on the EEG background remain uncertain. The objective of the present study is to investigate how VNS affects local and inter regional syncronization in different frequencies in pharmacoresistent partial epilepsy. Methods Digital recordings acquired in 11 epileptic subjects 1 year and 1 week before VNS surgery were compared with that obtained 1 month and 1 year after VNS activation. Power spectrum and synchronization were then analyzed and compared with an epileptic group of 10 patients treated with AEDs only. Results VNS decreases the synchronization of theta frequencies ( P<0.01), whereas it increases gamma power spectrum and synchronization (<0.001 and 0.01, respectively). Conclusions The reduction of theta frequencies and the increase in power spectrum and synchronization of gamma bands can be related to VNS anticonvulsant mechanism. In addition, gamma modulation could also play a seizure-independent role in improving attentional performances. Significance These results suggest that some antiepileptic mechanisms affected by VNS can be modulated by or be the reflection of EEG changes.

Vagus Nerve Stimulation Affects Pain Perception in Depressed Adults

Previous research suggests that vagus nerve stimulation (VNS) affects pain perception in epilepsy patients, with acute VNS decreasing pain thresholds and chronic VNS treatment increasing pain thresholds. However, no studies have investigated the effects of VNS on pain perception in chronically depressed adults, nor have controlled, systematic investigations been published on the differential effects of certain VNS device parameters on pain perception. The present study tried to replicate the results of previous research showing acute pronociceptive effects of VNS and determine the effects of various device parameter settings on pain tolerance. The present study also investigated the relationship among patients' levels of depression, duration of VNS treatment and VNS-induced changes in pain perception. A thermal pain challenge task was used to determine pain tolerance during VNS device activation using different combinations of VNS device parameter settings within subjects undergoing VNS therapy for chronic depression. Significant pronociceptive effects were found for acute VNS activation. Individual differences were found with respect to the VNS settings associated with the largest changes in pain perception. Severity of depression was inversely related to baseline pain tolerance, but depression severity was unrelated to VNS-induced acute changes in pain tolerance, as was the length of time participants had been undergoing VNS treatment. VNS appears to affect pain perception in depressed adults. Different VNS parameter settings may be associated with unique effects from patient to patient. More studies are needed to determine the long-term effects of VNS on pain perception.

Effects of vagus nerve stimulation on sleep-related breathing in epilepsy patients.

To describe the effects of vagus nerve stimulation (VNS) on sleep-related breathing in a sample of 16 epilepsy patients. Sixteen adults with medically refractory epilepsy (nine men, seven women, ages 21-58 years) underwent baseline polysomnograms (PSGs). Three months after VNS therapy was initiated, PSGs were repeated. In addition, patient 7 had a study with esophageal pressure monitoring, and patient 1 had a continuous positive airway pressure (CPAP) trial. Baseline PSGs: One of 16 patients had an apnea-hypopnea index (AHI) >5 (6.8). Treatment PSGs: Five of 16 patients had treatment AHIs >5. Respiratory events were more frequent during periods with VNS activation (on-time) than without VNS activation (off-time; p = 0.016). Follow-up studies: Esophageal pressure monitoring in patient 7 showed crescendos in esophageal pressure during VNS activation, supporting an obstructive pattern. The CPAP trial of patient 1 showed that all respiratory events were associated with VNS stimulation at low CPAP levels. They were resolved at higher CPAP levels. Treatment with VNS affects respiration during sleep and should be used with care, particularly in patients with preexisting obstructive sleep apnea. The AHI after VNS treatment remained <5 in the majority of patients and was only mildly elevated (<12) in five patients. In one patient, CPAP resolved VNS-related respiratory events.

Effects of vagus nerve stimulation on respiration during sleep: a pilot study.

Vagus nerve stimulation (VNS) is associated with respiratory effects such as hoarseness, dyspnea, and laryngeal irritation. The effects of VNS on sleep-related breathing in humans have not been reported previously. Four epilepsy patients underwent polysomnography (PSG) before and after 3 months of treatment with VNS. Two of the four patients also underwent follow-up PSG to assess the effects of changing stimulus parameters on sleep-related breathing. All patients showed consistent sleep-related decreases in airflow and effort coinciding with VNS activation, although most events did not meet laboratory criteria for apneas or hypopneas. Apneas and hypopneas were more frequent during VNS activation than during nonactivation. Apnea-hypopnea index (AHI) for three subjects during VNS treatment PSG was <5 apneas and hypopneas/hour. In one patient with obstructive sleep apnea (OSA) before VNS treatment, AHI rose from 4 (pretreatment) to 11.3 (treatment). In this patient and in another patient without clinically significant OSA, lowering stimulus frequency, but not stimulus intensity, pulse width, or on-time, ameliorated VNS-related apneas and hypopneas. VNS is associated with adverse changes in respiration during sleep. In patients without preexisting OSA, this VNS effect is probably not clinically significant. In patients with preexisting OSA, VNS should be administered with care. Lowering VNS stimulus frequency or prolonging off-time may prevent exacerbation of OSA.