Effects Of Vagus Nerve Stimulation Research Articles

Vagus nerve stimulation induces widespread cortical and behavioral activation

Vagus nerve stimulation (VNS) is used for management of a variety of neurological conditions, although the therapeutic mechanisms are not fully understood. Accumulating evidence suggests that VNS may modulate cortical state and plasticity through activation of broadly projecting neuromodulatory systems. Using a mouse model, we compared arousal-linked behaviors with dorsal cortical activity obtained with widefield and two-photon GCaMP6s calcium imaging and electrophysiological recordings. We observed robust and reliable cortical and behavioral dose-dependent activation in waking mice to VNS, including pupil dilation and, frequently, whisker movements and locomotion. Widefield calcium imaging and multiunit recording during VNS revealed that this observed increase in arousal state is coupled with a rapid and widespread increase in excitatory activity, including, but not limited to, activation of somatosensory, visual, motor, retrosplenial, and auditory cortical regions. Two-photon GCaMP6s calcium imaging of cholinergic and noradrenergic cortical axons revealed that VNS strongly activates these neuromodulatory systems. Importantly, VNS-evoked activation of neuromodulatory axons and excitatory neurons in the cortex persisted in mice under light anesthesia, in the absence of overt movement. Arousal state changes were abolished by vagus nerve transection, confirming that observed VNS effects were specific to nerve stimulation and triggered widespread activity above that which can be explained by motor activity. Taken together, our results support a model of VNS in which activation of subcortical structures leads to widespread activation of cortex and an increase in arousal state, at least partially due to the activation of cholinergic and noradrenergic modulatory pathways.

Trust your gut: vagal nerve stimulation in humans improves reinforcement learning.

Whereas the effect of vagal nerve stimulation on emotional states is well established, its effect on cognitive functions is still unclear. Recent rodent studies show that vagal activation enhances reinforcement learning and neuronal dopamine release. The influence of vagal nerve stimulation on reinforcement learning in humans is still unknown. Here, we studied the effect of transcutaneous vagal nerve stimulation on reinforcement learning in eight long-standing seizure-free epilepsy patients, using a well-established forced-choice reward-based paradigm in a cross-sectional, within-subject study design. We investigated vagal nerve stimulation effects on overall accuracy using non-parametric cluster-based permutation tests. Furthermore, we modelled sub-components of the decision process using drift-diffusion modelling. We found higher accuracies in the vagal nerve stimulation condition compared to sham stimulation. Modelling suggests a stimulation-dependent increase in reward sensitivity and shift of accuracy-speed trade-offs towards maximizing rewards. Moreover, vagal nerve stimulation was associated with increased non-decision times suggesting enhanced sensory or attentional processes. No differences of starting bias were detected for both conditions. Accuracies in the extinction phase were higher in later trials of the vagal nerve stimulation condition, suggesting a perseverative effect compared to sham. Together, our results provide first evidence of causal vagal influence on human reinforcement learning and might have clinical implications for the usage of vagal stimulation in learning deficiency.

Tinnitus treatment by vagus nerve stimulation: A systematic review.

Tinnitus is a phantom sensation of sound, which can have a negative impact on quality of life of those affected. No curative treatments are currently known. Neuromodulation by vagus nerve stimulation has emerged as a new treatment option for tinnitus, though till date the effectiveness remains unclear. Therefore, we aim to review the effect of vagus nerve stimulation on tinnitus distress and tinnitus symptom severity in patients with chronic tinnitus. We searched Pubmed, Embase and the Cochrane Library systematically for RCTs, observational studies and case studies on the effect of VNS treatment for tinnitus on October 29, 2019. Studies including adult patients with subjective tinnitus, comparing transcutaneous or implantable VNS to placebo or no treatment or before and after application of VNS treatment on tinnitus distress and tinnitus symptom severity measured with a validated questionnaire were eligible. The risk of bias was assessed with the appropriate tool for each type of study. Our search identified 9 primary studies of which 2 RCTs, 5 cohort studies and 2 case series or reports. 5 studies used transcutaneous VNS treatment and 4 used implanted VNS treatment. 6 studies combined VNS treatment with sound therapy. There was a serious risk of bias in all studies, especially on confounding. Most studies reported a small decrease in tinnitus distress or tinnitus symptom severity. Due to methodological limitations and low reporting quality of the included studies, the effect of VNS on tinnitus remains unclear. To draw conclusions for which patient population and to what extent (t)VNS is beneficial in the treatment of tinnitus, a randomised controlled trial should be considered.

Treatment of Super-Refractory Status Epilepticus: A Review.

Purpose:Super-refractory status epilepticus (SRSE) presents management challenges due to the absence of randomized controlled trials and a plethora of potential medical therapies. The literature on treatment options for SRSE reports variable success and quality of evidence. This review is a sequel to the 2020 American Epilepsy Society (AES) comprehensive review of the treatment of convulsive refractory status epilepticus (RSE).Methods:We sought to determine the effectiveness of treatment options for SRSE. We performed a structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) for studies on reported treatments of SRSE. We excluded antiseizure medications (ASMs) covered in the 2016 AES guideline on the treatment of established SE and the convulsive RSE comprehensive review of the 2020 AES. Literature was reviewed on the effectiveness of vagus nerve stimulation, ketogenic diet (KD), lidocaine, inhalation anesthetics, brain surgery, therapeutic hypothermia, perampanel, pregabalin (PGB), and topiramate in the treatment of SRSE. Two authors reviewed each therapeutic intervention. We graded the level of the evidence according to the 2017 classification scheme of the American Academy of Neurology.Results:For SRSE (level U; 39 class IV studies total), insufficient evidence exists to support that perampanel, PGB, lidocaine, or acute vagus nerve stimulation (VNS) is effective. For children and adults with SRSE, insufficient evidence exists to support that the KD is effective (level U; 5 class IV studies). For adults with SRSE, insufficient evidence exists that brain surgery is effective (level U, 7 class IV studies). For adults with SRSE insufficient, evidence exists that therapeutic hypothermia is effective (level C, 1 class II and 4 class IV studies). For neonates with hypoxic-ischemic encephalopathy, insufficient evidence exists that therapeutic hypothermia reduces seizure burden (level U; 1 class IV study). For adults with SRSE, insufficient evidence exists that inhalation anesthetics are effective (level U, 1 class IV study) and that there is a potential risk of neurotoxicity.Conclusion:For patients with SRSE insufficient, evidence exists that any of the ASMs reviewed, inhalational anesthetics, ketogenic diet, acute VNS, brain surgery, and therapeutic hypothermia are effective treatments. Data supporting the use of these treatments for SRSE are scarce and limited mainly to small case series and case reports and are confounded by differences in patients’ population, and comedications, among other factors.

The thalamus-precentral gyrus functional connectivity changes in epilepsy patients following vagal nerve stimulation

Vagal nerve stimulation (VNS) is an effective treatment for patients with drug-resistant epilepsy who are unsuitable for surgical epilepsy treatment. However, the mechanism of action of VNS remains unclear, and the efficacy of VNS treatment regarding seizure frequency reduction cannot be assessed before surgery. This study measured changes in functional connectivity between thalamus and precentral gyrus which are activated as vital targets of deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS) using resting-state functional MRI to evaluate the effects of VNS. 16 epilepsy patients who underwent VNS were collected and scanned by resting-state functional MRI before and after operation. The functional connections (regions of interest: thalamus, precentral gyrus) were examined. After three months of stimulation, there were eight responders (≥50 % seizure reduction) and eight non-responders to VNS. No significant difference in thalamus-precentral gyrus functional connectivity was found between responders and nonresponders before operation. Enhanced functional connections were observed between bilateral thalamus and bilateral precentral gyrus in responders, which decreased in nonresponders, while functional connections between bilateral thalamus decreased in both responders and nonresponders. Short-term stimulation may cause thalamus-precentral gyrus functional connectivity changes in DRE patients, and control seizures by enhancing functional connections between bilateral thalamus and bilateral precentral gyrus.

Graded recruitment of pupil-linked neuromodulation by parametric stimulation of the vagus nerve

Vagus nerve stimulation (VNS) is thought to affect neural activity by recruiting brain-wide release of neuromodulators. VNS is used in treatment-resistant epilepsy, and is increasingly being explored for other disorders, such as depression, and as a cognitive enhancer. However, the promise of VNS is only partially fulfilled due to a lack of mechanistic understanding of the transfer function between stimulation parameters and neuromodulatory response, together with a lack of biosensors for assaying stimulation efficacy in real time. We here develop an approach to VNS in head-fixed mice on a treadmill and show that pupil dilation is a reliable and convenient biosensor for VNS-evoked cortical neuromodulation. In an ‘optimal’ zone of stimulation parameters, current leakage and off-target effects are minimized and the extent of pupil dilation tracks VNS-evoked basal-forebrain cholinergic axon activity in neocortex. Thus, pupil dilation is a sensitive readout of the moment-by-moment, titratable effects of VNS on brain state.

Characterization of opioidergic mechanisms related to the anti-migraine effect of vagus nerve stimulation

Vagus nerve stimulation (VNS) is a promising neuromodulation approach used in the treatment of migraine, whose therapeutic mechanism is largely unknown. Previous studies suggest that VNS's anti-nociceptive effects may, in part, involve engaging opioidergic mechanisms. We used a validated preclinical model of head pain, with good translational outcomes in migraine, acute intracranial-dural stimulation, which has responded to invasive VNS.We tested the effects of μ (MOR), δ (DOR) and κ (KOR) opioid receptor agonists in this model, and subsequently the effects of opioid receptor antagonists against VNS-mediated neuronal inhibition. MOR, DOR, and KOR agonists all inhibited dural-evoked trigeminocervical neuronal responses. Both DOR and KOR agonists also inhibited ongoing spontaneous firing of dural responsive neurons. Both DOR and KOR agonists were more efficacious than the MOR agonist in this model. We confirm the inhibitory effect of invasive VNS and demonstrate that this effect was prevented by a broad-spectrum opioid receptor antagonist, and by a highly selective DOR antagonist. Our data confirm the role of MOR in dural-trigeminovascular neurotransmission and additionally provide evidence of a role of both DOR and KOR in dural-nociceptive transmission of trigeminocervical neurons. Further, the results here provide evidence of engagement of opioidergic mechanisms in the therapeutic action of VNS in headache, specifically the DOR. These studies provide further support for the important role of the DOR in headache mechanisms, and as a potential therapeutic target. The data begin to dissect the mode of action of the analgesic effects of VNS in the treatment of primary headache disorders.

Effect of Long-Term Treatment with Vagus Nerve Stimulation on Mood and Quality of Life in Korean Patients with Drug-Resistant Epilepsy.

Background and PurposeThis study aimed to determine the long-term effects of vagus nerve stimulation (VNS) treatment on suicidality, mood-related symptoms, and quality of life (QOL) in patients with drug-resistant epilepsy (DRE). We also investigated the relationships among these main effects, clinical characteristics, and VNS parameters.MethodsAmong 35 epilepsy patients who underwent VNS implantation consecutively in our epilepsy center, 25 patients were recruited to this study for assessing the effects of VNS on suicidality, mood-related symptoms, and QOL. The differences in these variables between before and after VNS treatment were analyzed statistically using paired t-tests. Multiple linear regression analyses were also performed to determine how the patients' demographic and clinical characteristics influenced the variables that showed statistically significant changes after long-term VNS treatment.ResultsAfter VNS, our patients showed significant improvements not only in the mean seizure frequency but also in suicidality, depression, and QOL. The reduction in depression was associated with the improvement in QOL and more-severe depression at baseline. The reduction in suicidality was associated with higher suicidality at baseline, smaller changes in depression, and less-severe depression at baseline. Improved QOL was associated with lower suicidality at baseline.ConclusionsThis study found that VNS decreased the mean seizure frequency in patients with DRE, and also improved their depression, suicidality, and QOL. These results provide further evidence for therapeutic effect of VNS on psychological comorbidities of patients with DRE.

The effectiveness of vagus nerve stimulation after failed surgical treatment of pharmacoresistant epilepsy

According to the WHO, about 50 million people in the world suffer from epilepsy, while 20–40 % are resistant to antiepileptic drugs and need alternative treatment methods. The arsenal of neurosurgeons includes a wide range of operations that have proven effectiveness in the fight against pharmacoresistant epilepsy. Such a promising type of treatment as vagus nerve stimulation can be used both with contraindicated resection surgery and after it. Currently, the field of VNS therapy continues to be explored, including the efficiency and rationality of its use.

Vagus Nerve Stimulation Induces Widespread Cortical and Behavioral Activation

Vagus nerve stimulation (VNS) is used for management of a variety of neurological conditions, although the therapeutic mechanisms are not fully understood. Accumulating evidence suggests that VNS may modulate cortical state and plasticity through activation of broadly projecting neuromodulatory systems. Using a mouse model, we compared arousal-linked behaviors with dorsal cortical activity obtained with widefield and 2-photon GCaMP6s calcium imaging and electrophysiological recordings. We observed robust and reliable cortical and behavioral dose-dependent activation in waking mice to VNS, including pupil dilation and frequently, whisker movements and locomotion. Widefield calcium imaging and multiunit recording during VNS revealed that this observed increase in arousal state is coupled with a rapid and widespread increase in excitatory activity, including, but not limited to, activation of visual, motor, retrosplenial, auditory, and barrel cortical regions. Two-photon GCaMP6s calcium imaging of cholinergic and noradrenergic cortical axons revealed that VNS strongly activates these neuromodulatory systems. Importantly, VNS-evoked activation of neuromodulatory axons and excitatory neurons in the cortex persisted in mice under light anesthesia, in the absence of overt movement, and arousal state changes were abolished by vagus nerve transection, confirming that observed VNS effects were specific to nerve stimulation and triggered widespread activity above that which can be explained by motor activity. Taken together, our results support a model of VNS in which activation of subcortical structures leads to widespread activation of cortex and an increase in arousal state, at least partially due to the activation of cholinergic and noradrenergic modulatory pathways.

Sleep disordered breathing in children receiving vagus nerve stimulation therapy

ObjectiveThe effects of vagus nerve stimulation (VNS) on sleep disordered breathing (SDB) have been reported in limited case series. Detailed studies, particularly in the pediatric population, have not been performed. The primary purpose of this study is to describe clinical characteristics, polysomnographic findings, and management of children treated with VNS. MethodsA retrospective review of medical records and polysomnography data was performed in patients ages 0–20 years old receiving VNS therapy for refractory epilepsy at Cincinnati Children's Hospital Medical Center. Results22 subjects met the inclusion criteria. 50% were male. The mean age at the time of VNS insertion was 8.4 ± 4.0 years. The mean age at the first PSG was 10.6 ± 4.3 years. Common presentations to sleep clinics included snoring (77.3%), frequent nighttime awakening (68.1%), and parasomnias (63.6%). The median apnea-hypopnea index (AHI) was 4.5/hr (IQR 3.0–13.1) and the median obstructive index (OI) was 4.1/hr (1.5–12.8). Obstructive sleep apnea (OSA) was diagnosed after VNS insertion in 19 patients (86.4%), 8 of which (36.3%) had severe OSA. Six patients (27.3%) had significant hypoventilation. For management, 6 patients (27.2%) were treated with bilevel PAP, 3 patients (13.6%) with CPAP, 2 patients (9.1%) with ventilator, 4 patients (18.2%) with upper airway surgeries, and 9 patients (40.9%) received medications only. ConclusionsSDB is common in pediatric patients with medically refractory epilepsy managed with VNS who were referred to sleep medicine clinics. Both OSA and nocturnal alveolar hypoventilation are relatively common in this population. Management of SDB often involves the use of positive airway pressure therapy or upper airway surgeries. Further studies are needed to assess the prevalence, risk factors, and the effect of treatments on epilepsy control. This study highlights the need for screening of SDB prior to and following VNS implantation.

Preliminary analysis of the effect of vagus nerve stimulation in the treatment of children with intractable epilepsy.

BACKGROUNDImplant vagus nerve stimulation is an adjunctive treatment for intractable epilepsy when patients are not suitable for resective surgery.AIMTo identify the safety and efficacy of vagus nerve stimulation in children with intractable epilepsy and analyze the effects on different epilepsy syndromes.METHODSEligible children with intractable epilepsy were admitted to the study. We collected data from preoperative assessments as the baseline. During the follow-up time, we recorded the process of seizures (frequency, duration, and seizure type), the changes of drugs or parameters, the complications, etc. The mean reduction rate of seizures, response rate, and McHugh scale were chosen as the outcomes.RESULTSA total of 213 patients were implanted with Tsinghua Pins vagus nerve stimulators, and the average age was 6.6 years. In the follow-up time of postoperative 3 mo, 6 mo, 12 mo, 18 mo, and 24 mo, the average reduction rate was 30.2%, 49.5%, 56.3%, 59.4%, and 63.2%, while the response rate was 21.8%, 62.5%, 57.1%, 69.2%, and 70.7%. In addition, implanted vagus nerve stimulation had different effects on epilepsy syndromes. The reduction rate of West syndrome increased from 36.4% (postoperative 6 m) to 74.3% (postoperative 24 m). The reduction rate of Lennox-Gastaut syndrome improved from 25.4% to 73.1% in 24 mo. The chi-square test of the five efficacy grades showed P < 0.05. The comparison between the 3-mo follow-up and the 6-mo follow-up showed P < 0.05, and the comparison between the 6-mo follow-up and the 24-mo follow-up showed P > 0.05.CONCLUSIONVagus nerve stimulation is safe and effective in children with intractable epilepsy, and the seizure reduction occurred in a time-dependent manner. Moreover, patients with West syndrome may get the most benefits.

Preliminary analysis of the effect of vagus nerve stimulation in the treatment of children with intractable epilepsy

Preliminary analysis of the effect of vagus nerve stimulation in the treatment of children with intractable epilepsy

The Effectiveness of Vagus Nerve Stimulation in Drug-Resistant Epilepsy Correlates with Vagus Nerve Stimulation-Induced Electroencephalography Desynchronization.

Introduction: VNS is an adjunctive neuromodulation therapy for patients with drug-refractory epilepsy. The antiseizure effect of VNS is thought to be related to a diffuse modulation of functional connectivity but remains to be confirmed.Aim: To investigate electroencephalographic (EEG) metrics of functional connectivity in patients with drug-refractory epilepsy treated by vagus nerve stimulation (VNS), between VNS-stimulated “ON” and nonstimulated “OFF” periods and between responder (R) and nonresponder (NR) patients.Methods: Scalp-EEG was performed for 35 patients treated by VNS, using 21 channels and 2 additional electrodes on the neck to detect the VNS stimulation. Patients were defined as VNS responders if a reduction of seizure frequency of ∼50% was documented. We analyzed the synchronization in EEG time series during “ON” and “OFF” periods of stimulation, using average phase lag index (PLI) in signal space and phase-locking value (PLV) between 10 sources. Based on graph theory, we computed brain network models and analyzed minimum spanning tree (MST) for responder and nonresponder patients.Results: Among 35 patients treated by VNS for a median time of 7 years (range 4 months to 22 years), 20 were R and 15 were NR. For responder patients, PLI during ON periods was significantly lower than that during OFF periods in delta (p = 0.009), theta (p = 0.02), and beta (p = 0.04) frequency bands. For nonresponder patients, there were no significant differences between ON and OFF periods. Moreover, variations of seizure frequency with VNS correlated with the PLI OFF/ON ratio in delta (p = 0.02), theta (p = 0.04), and beta (p = 0.03) frequency bands. Our results were confirmed using PLV in theta band (p < 0.05). No significant differences in MST were observed between R and NR patients.Conclusion: The correlation between VNS-induced interictal EEG time-series desynchronization and decrease in seizure frequency suggested that VNS therapeutic impact might be related to changes in interictal functional connectivity.Impact statementElectroencephalography (EEG) desynchronization has been proposed to be a mechanism for antiepileptic effect of vagus nerve stimulation (VNS). We measured interictal EEG time-series synchronization during stimulated (ON) and nonstimulated (OFF) periods in epileptic patients treated by VNS. Phase lag index differences between ON and OFF periods were measured in delta, theta, and beta bands only in responder patients. To our knowledge, our study is the first to statistically correlate interictal cortical desynchronization during ON periods with reduction in seizure frequency. Our result supports the hypothesis that the antiseizure effect of VNS is mediated by cortical desynchronization.

PMH19 Cost-Effectiveness of Vagus Nerve Stimulation for Treatment-Resistant Depression in the United Kingdom

Treatment-resistant depression (TRD) is a debilitating condition with a significant impact on patients and carers, and health care spending. Treatment resistance occurs in approximately 30% of individuals affected by Major Depressive Disorder. This analysis explored the potential cost-effectiveness of introducing vagus nerve stimulation (VNS) adjunctive to treatment as usual (TAU) for patients with TRD who have failed on ≥4 adequate anti-depressant treatments in England and Wales. A Markov model simulated patient transitions between health states defined by type of treatment, battery status and disease severity, as defined by Montgomery–Åsberg Depression Rating Scale score. Effectiveness was based on individual patient data from the D-21 dosing trial and the D-23 observational study assessing the effectiveness of VNS plus TAU compared to TAU alone. Hypothetical patients included those with moderate and severe depression at baseline, reflecting the population that would be eligible for VNS. The model had a 10-year time horizon and took a UK NHS perspective. Longer time horizons were also explored, as was a societal perspective. Costs and benefits were discounted at a rate of 3.5%. One-way deterministic, probabilistic and scenario analyses were undertaken to test various model inputs. When considering direct costs, the total cost of the VNS strategy was £42,589 compared to £29,928 for TAU. VNS generated 0.42 incremental quality-adjusted life-years (QALYs) compared to TAU, giving an incremental cost-effectiveness ratio (ICER) of £29,995 per QALY gained. When societal costs were considered, the VNS strategy dominated. In the probabilistic sensitivity analysis, VNS had a 50% probability of being cost-effective at a willingness-to-pay threshold of £30,000 per QALY. Extending the time horizon of the analysis to 20 years resulted in an ICER of £25,764. This analysis shows that VNS in addition to TAU could represent a cost-effective option for patients with TRD in the UK.

Transcutaneous Vagus Nerve Stimulation in Humans Induces Pupil Dilation and Attenuates Alpha Oscillations

Vagus nerve stimulation (VNS) is widely used to treat drug-resistant epilepsy and depression. While the precise mechanisms mediating its long-term therapeutic effects are not fully resolved, they likely involve locus coeruleus (LC) stimulation via the nucleus of the solitary tract, which receives afferent vagal inputs. In rats, VNS elevates LC firing and forebrain noradrenaline levels, whereas LC lesions suppress VNS therapeutic efficacy. Noninvasive transcutaneous VNS (tVNS) uses electrical stimulation that targets the auricular branch of the vagus nerve at the cymba conchae of the ear. However, the extent to which tVNS mimics VNS remains unclear. Here, we investigated the short-term effects of tVNS in healthy human male volunteers (n= 24), using high-density EEG and pupillometry during visual fixation at rest. We compared short (3.4 s) trials of tVNS to sham electrical stimulation at the earlobe (far from the vagus nerve branch) to control for somatosensory stimulation. Although tVNS and sham stimulation did not differ in subjective intensity ratings, tVNS led to robust pupil dilation (peaking 4–5 s after trial onset) that was significantly higher than following sham stimulation. We further quantified, using parallel factor analysis, how tVNS modulates idle occipital alpha (8–13Hz) activity identified in each participant. We found greater attenuation of alpha oscillations by tVNS than by sham stimulation. This demonstrates that tVNS reliably induces pupillary and EEG markers of arousal beyond the effects of somatosensory stimulation, thus supporting the hypothesis that tVNS elevates noradrenaline and other arousal-promoting neuromodulatory signaling, and mimics invasive VNS.SIGNIFICANCE STATEMENTCurrent noninvasive brain stimulation techniques are mostly confined to modulating cortical activity, as is typical with transcranial magnetic or transcranial direct/alternating current electrical stimulation. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to stimulate subcortical arousal-promoting nuclei, though previous studies yielded inconsistent results. Here we show that short (3.4 s) tVNS pulses in naive healthy male volunteers induced transient pupil dilation and attenuation of occipital alpha oscillations. These markers of brain arousal are in line with the established effects of invasive VNS on locus coeruleus–noradrenaline signaling, and support that tVNS mimics VNS. Therefore, tVNS can be used as a tool for studying how endogenous subcortical neuromodulatory signaling affects human cognition, including perception, attention, memory, and decision-making; and also for developing novel clinical applications.

Sex Differences in Vagus Nerve Stimulation Effects on Rat Cardiovascular and Immune Systems.

BackgroundInvestigations into the benefits of vagus nerve stimulation (VNS) through pre-clinical and clinical research have led to promising findings for treating several disorders. Despite proven effectiveness of VNS on conditions such as epilepsy and depression, understanding of off-target effects and contributing factors such as sex differences can be beneficial to optimize therapy design.New MethodsIn this article, we assessed longitudinal effects of VNS on cardiovascular and immune systems, and studied potential sex differences using a rat model of long-term VNS. Rats were implanted with cuff electrodes around the left cervical vagus nerve for VNS, and wireless physiological monitoring devices for continuous monitoring of cardiovascular system using electrocardiogram (ECG) signals. ECG morphology and heart rate variability (HRV) features were extracted to assess cardiovascular changes resulting from VNS in short-term and long-term timescales. We also assessed VNS effects on expression of inflammatory cytokines in blood during the course of the experiment. Statistical analysis was performed to compare results between Treatment and Sham groups, and between male and female animals from Treatment and Sham groups.ResultsConsiderable differences between male and female rats in cardiovascular effects of VNS were observed in multiple cardiovascular features. However, the effects seemed to be transient with approximately 1-h recovery after VNS. While short-term cardiovascular effects were mainly observed in male rats, females in general showed more significant long-term effects even after VNS stopped. We did not observe notable changes or sex differences in systemic cytokine levels resulting from VNS.Comparison With Existing MethodsCompared to existing methods, our study design incorporated wireless physiological monitoring and systemic blood cytokine level analysis, along with long-term VNS experiments in unanesthetized rats to study sex differences.ConclusionThe contribution of sex differences for long-term VNS off-target effects on cardiovascular and immune systems was assessed using awake behaving rats. Although VNS did not change the concentration of inflammatory biomarkers in systemic circulation for male and female rats, we observed significant differences in cardiovascular effects of VNS characterized using ECG morphology and HRV analyses.

Efficacy of VNS for Drug-Resistant Epilepsy in Structural Brain Lesions

Background: Vagus nerve stimulation (VNS) has been used for the treatment of drug-resistant epilepsy, especially in patients who are not candidates for surgical intervention. In fact, it was approved by the US FDA in 1997 as an adjunctive treatment for medically intractable epilepsy. Objective: In this study, we investigated the efficacy of VNS in drug-resistant epilepsy associated with structural brain lesions (SBLs). Methods: We retrospectively analyzed the effect of VNS on 25 patients diagnosed with intractable epilepsy-associated SBL, and compared the results to 19 patients with intractable epilepsy and normal neuroimaging. All patients underwent VNS insertion at the National Neurosciences Institute, King Fahad Medical City (Riyadh, Saudi Arabia) between 2008 and 2018. Results: The response rate (RR) for patients with drug-resistant epilepsy-associated SBL was 24% after 3 months, 36% after 6 months, and 48% after 1 year, reaching 76% over time. The mean follow-up period was 63.3 months. For non-SBL patients, the RR was 10.5% after 3 months, 36.8% after 6 months, and 47.4% after 1 year, reaching 73.7% over time. The mean follow-up period was 59.2 months. There was no statistically significant difference between the two groups regarding RR, VNS settings, and other parameters, including anti-epileptic drug use and demographics data. Conclusion: VNS is strongly considered for intractable epilepsy in SBL patients, especially if they are not candidates for surgical intervention. Over time, those patients will receive increased benefits from VNS therapy.

Non-invasive vagus nerve stimulation attenuates proinflammatory cytokines and augments antioxidant levels in the brainstem and forebrain regions\xa0of Dahl salt sensitive rats

The anti-inflammatory effects of vagus nerve stimulation are well known. It has recently been shown that low-level, transcutaneous stimulation of vagus nerve at the tragus (LLTS) reduces cardiac inflammation in a rat model of heart failure with preserved ejection fraction (HFpEF). The mechanisms by which LLTS affect the central neural circuits within the brain regions that are important for the regulation of cardiac vagal tone are not clear. Female Dahl salt-sensitive rats were initially fed with either low salt (LS) or high salt (HS) diet for a period of 6 weeks, followed by sham or active stimulation (LLTS) for 30 min daily for 4 weeks. To study the central effects of LLTS, four brainstem (SP5, NAb, NTS, and RVLM) and two forebrain sites (PVN and SFO) were examined. HS diet significantly increased the gene expression of proinflammatory cytokines in the SP5 and SFO. LLTS reversed HS diet-induced changes at both these sites. Furthermore, LLTS augmented the levels of antioxidant Nrf2 in the SP5 and SFO. Taken together, these findings suggest that LLTS has central anti-inflammatory and antioxidant properties that could mediate the neuromodulation of cardiac vagal tone in the rat model of HFpEF.

Vagus Nerve Stimulation Provides Multiyear Improvements in Autonomic Function and Cardiac Electrical Stability in the ANTHEM-HF Study

Patients with heart failure with reduced left ventricular ejection fraction (LVEF) (HFrEF) experience long-term deterioration of autonomic function and cardiac electrical stability linked to increased mortality risk. The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF) trial reported improved heart rate variability (HRV) and heart rate turbulence (HRT) and reduced T-wave alternans (TWA) after 12 months of vagus nerve stimulation (VNS). We investigated whether the benefits of chronic VNS persist in the long term. Effects of chronic VNS on heart rate, HRV, HRT, TWA, R-wave and T-wave heterogeneity (RWH, TWH), and nonsustained ventricular tachycardia (NSVT) incidence were evaluated in all ANTHEM-HF patients with ambulatory ECG data at 24 and 36 months (n = 25). Autonomic markers improved significantly at 24 and 36 months compared to baseline [heart rate, square root of the mean squared differences of successive normal-to-normal intervals (rMSSD), standard deviation of the normal-to-normal intervals (SDNN), HF-HRV, HRT slope, P < 0.05]. Peak TWA levels remained reduced at 24 and 36 months (P < 0.0001). Reductions in RWH and TWH at 6 and 12 months persisted at 24 and 36 months (P < 0.01). NSVT decreased at 12, 24, and 36 months (P < 0.025). No sudden cardiac deaths, ventricular fibrillation, or sustained ventricular tachycardia occurred. In symptomatic patients with HFrEF, chronic VNS appears to confer wide-ranging, persistent improvements in autonomic tone (HRV), baroreceptor sensitivity (HRT), and cardiac electrical stability (TWA, RWH, TWH).