Effects Of Vagus Nerve Stimulation Research Articles

Intermittent vagus nerve stimulation allows preventing the “escape” effect of heart rhythm changes

Background.Vagus nerve stimulation has been proposed for the treatment of a number of diseases. The positive effects of vagus nerve stimulation on ischemic and reperfusion myocardial injury has been tested in experimental models. However, the escape effect of vagus activation on heart rate and the methodology to overcome this effect have not been reported properly.Objective. The purpose of the study is to evaluate parameters of prolonged stimulation that decrease heart rate and allow overcoming the escape effect of vagus nerve activation.Design and methods. We used Wistar rats (n = 9). Cervical section was performed under general anesthesia. Left vagus nerve isolated from adjacent tissue was contacted with custom stimulation electrodes and a custom pulse generator. Blood pressure was measured in the right common carotid artery. Limb electrocardiogram was continuously recorded. First, stimulation parameters repeatedly evoking vagal reaction (decrease in heart rate) without nerve damage were evaluated. Second, parameters of intermittent stimulation that allowed repeat and consistent heart rate decrease were assessed.Results. During experiments, in 5 animals the following parameters leading to sustained 30 ± 20 % heart rate reduction were found: rectangular pulse, 30 Hz, 0,5 ms, 1–2 V (0,6– 0,8 mA). Stimulation with 50 Hz frequency led to nerve damage in 1 case. Stimulation with 20 Hz frequency led to heart rate over-suppression of heart rate and blood pressure. Intermittent nerve stimulation was tested in 4 animals and led to repeated heart rate decrease by 38 ± 15 %. The parameters which helped to avoid escape effect on heart rate change were the following: the length of stimulation episode of 45 s and interruption of stimulation for 15 s.Conclusion. Intermittent electrical stimulation evokes vagal reactions on heart rate and allows overcoming the escape effect of vagal activation.

Effect of vagus nerve stimulation in the treatment of pediatric intractable epilepsy: A preliminary analysis

Effect of vagus nerve stimulation in the treatment of pediatric intractable epilepsy: A preliminary analysis

Microscopic magnetic stimulation of the cervical vagus nerve

Introduction: Electrical vagus nerve stimulation (VNS) is an FDA-approved treatment for drug-resistant epilepsy, depression, and headache. However, oxidation/reduction reactions at the electrode tissue interface can result in damage and reduce the efficacy of stimulation. Micro-magnetic stimulation (μMS) of the vagus nerve has the potential to be an alternative to electrical VNS. μMS is accomplished by running alternating current through a sub-millimeter coil to produce time-varying magnetic fields which can in turn induce electrical fields, leading to neuronal activation. The small size of the coils involved leads to high spatial resolution of μMS. μMS is distinct from electrical stimulation in that it can activate axons based on the particular coil orientation, and in that it does not require charge-balanced stimulation waveform shapes, which are needed in electrical stimulation to avoid electrophoresis. The coils used in μMS do not undergo oxidation/reduction reactions and are compatible with imaging devices such as MRI. Thus, μMS represents a groundbreaking step forward from the traditional electrical stimulation of neurons. Here, we describe the effect of micro-magnetic VNS (μM-VNS) on physiological parameters in rats.

Adaptive intensity vagus nerve stimulation effect on plasticity in primary auditory cortex

Adaptive intensity vagus nerve stimulation effect on plasticity in primary auditory cortex

Impacts of Renal Denervation and Vagus Nerve Stimulation on Acute Renal Failure Induced by Renal Ischemia Reperfusion injury in Rat Model

Ischemia-Reperfusion Injury (IRI) is characterized by temporary cessation followed by restoration of blood supply and re-oxygenation of a certain organ. In the kidney, IRI contributes to Acute Kidney Injury (AKI) with rapid kidney damage and high morbidity and mortality rates. A surgical or drug-induced blockage of renal sympathetic nerve prevents, partially, the development of IR-induced AKI. Modulation of the Cholinergic Anti-Inflammatory Pathway (CAP) by Vagal Nerve Stimulation (VNS) has also a delayed but effective impact in renal IRI. However, the combined effect of renal sympathectomy and VNS had not been well investigated. Objectives: This work aimed at investigating the combined effect of VNS and Renal Denervation (RDN) in preventing deleterious effects of IRI in rats compared to the effects obtained by RDN alone and to elucidate the possible mechanisms. Methods: 32 adult male albino rats were equally allocated into four groups, sham group, IRI group, RDN group subjected to RDN before IRI and a group subjected to RDN and VNS before IRI. Results: Compared to the sham group, renal IRI led to the elevation of BUN, serum creatinine and MDA levels, it also elevated TNFα and reduced GPX activity and nitrate levels in the renal tissue. In addition, IRI lowered BCL2 in the immune-histochemical study and caused renal damage as observed by the histological light and electron microscopic examination. On the other hand, RDN demonstrated partial correction while, a combination of RDN and VNS demonstrated nearly optimum recovery of renal functions, oxidant/antioxidant balance, inflammatory markers as well as marked amelioration of immunohistochemical, structural and ultra-structural studies. Conclusion: VNS augmented and accelerated the renoprotective effects of RDN owing to its antioxidant, antiinflammatory as well as anti-apoptotic effects. Additionally, when VNS was combined to RDN, the protection against acute renal failure induced by IRI was rapid and effective.

Vagus nerve stimulation therapy for post-encephalitic intractable epilepsy in children

Objective To evaluate the effect of vagus nerve stimulation (VNS) on post-encephalitic intractable epilepsy and the improvement of postoperative cognitive function and quality of life. Methods The patients with post-encephalitic epilepsy in Sanbo Brain Hospital, Capital Medical University from January 2008 to December 2016 were selected.A single center and retrospective study method was used to evaluate the cognitive function, social function of preoperative and postoperative and postoperative seizure classification.The follow-up time points included preoperative, posto-perative in 6 months, 1 year after operation and postoperative annual review. Results A total of 43 patients were followed up, including 19 females and 24 males, with an average age of (9.37± 4.18) years old.The time of follow-up was (43.90 ± 33.04) months.According to Engel classification: Grade Ⅰ 3 cases (7.0%), grade Ⅱ 3 cases (7.0%), grade Ⅲ 14 cases (32.6%), grade Ⅳ 21 cases (48.8%). According to McHugh classification: Grade Ⅰ 8 cases (18.6%), grade Ⅱ 12 cases (28%), grade Ⅲ 11 cases (25.5%), grade Ⅳ 6 cases (14.0%), grade Ⅴ 4 cases (9.3%). Speech improvement of postoperative: significant improvement in 3 cases (7.0%), slightly improved in 17 cases (39.6%); interpersonal communication improvement of postoperative: significantly increased 7 cases (16.4%), slightly improved 16 cases(37.2%); learning/working ability improvement of postoperative: significantly improved 6 cases(14.0%), slightly increased 14 cases(32.6%). The postoperative VIQ (6.21±5.02) scores, PIQ (7.28±6.10) scores, FIQ (2.93±3.74) scores and MQ were (4.81±2.98) scores higher than preoperative. Conclusions VNS can effectively improve the seizures of post-encephalitic epilepsy as well as the children′s quality of life, cognition and social function. Key words: Post-encephalitic epilepsy; Vagus nerve stimulation; Cognitive function; Follow-up study

A 6-Year Follow-up Study of Vagus Nerve Stimulation Effect on Quality of Life in Treatment-Resistant Depression: A Pilot Study.

Treatment-resistant depression (TRD) carries a major burden on those affected by this disease and significantly impacts their quality of life (QOL). Vagus nerve stimulation (VNS) has showed promising results on symptoms, but its impact on QOL remains underresearched. This study aims to evaluate the long-term effects of VNS on both QOL and clinical symptoms for TRD patients, through a naturalistic 6-year follow-up. Outpatients with confirmed TRD were enrolled to receive VNS. None of the patients enrolled left the study or was lost at follow-up. Patients were evaluated at 1, 3, 6, 12, 24, 36, 48, 60, and 72 months for a total of 10 assessments using the 36 item Short Form questionnaire, Hamilton Rating Scale for Depression and Hamilton Anxiety Rating Scale. Ten patients were enrolled with a mean age of 50 years. This study shows a clinically and statistically significant improvement of the mental QOL (P = 0.012), physical QOL (P < 0.002), depressive symptoms (P < 0.001), and anxiety symptoms (P < 0.001). This long-term naturalistic study is the first to demonstrate that the therapeutic effect of VNS on TRD goes beyond clinical symptoms to improve the daily QOL of those affected.

Estimating Long-Term Vagus Nerve Stimulation Effectiveness: Accounting for Antiepileptic Drug Treatment Changes

To investigate the effectiveness of vagus nerve stimulation (VNS) in combination with pharmacological therapy in a longitudinal retrospective study at a single center. Data from 130 consecutive patients implanted with a VNS device between the years 2000 and 2013 was analyzed. Seizure frequency and pharmacological antiepileptic drug (AED) treatments were recorded prior to as well as at one, two, and five years after VNS implantation. Median age at epilepsy onset was five years and mean years from diagnosis to VNS implantation was 16.5 years. There was a significant seizure reduction overall (all p < 0.001). The responder (≥50% seizure frequency reduction) rate increased from 22.1 to 43.8% between the first and fifth year for the cohort as a whole, with the largest increase between the first and second year (22.1-38.1%) and regardless of AED changes. VNS effectiveness did not differ between patients who altered or remained on the same AEDs. Patients were treated with a median of three AEDs throughout the study and the number of AEDs significantly increased after two (p = 0.007) and five (p = 0.001) years. VNS is a well-tolerated palliative neuromodulatory treatment for drug resistant epilepsy with a 43.8% seizure reduction after five years. Our data supports the idea that VNS effectiveness increases with time. Therefore we suggest that VNS should be evaluated for at least two years after implantation. AED changes should try to be kept to a minimum during evaluation in order to determine the effectiveness of VNS.

Cervical vagal nerve stimulation impairs glucose tolerance and suppresses insulin release in conscious rats.

Previously, we reported that cervical vagal nerve stimulation (VNS) increases blood glucose levels and inhibits insulin secretion in anesthetized rats through afferent signaling. Since afferent signaling is also thought to mediate the therapeutic effects of VNS in patients with therapy‐refractory epilepsy and major depression, the question arises if patients treated with VNS develop impaired glucose tolerance. Thus, we hypothesized that cervical VNS impairs glucose tolerance in conscious rats. Rats (n = 7) were instrumented with telemetric blood pressure sensors and right‐ or left‐sided cervical vagal nerve stimulators (3 V, 5 Hz, 1 msec pulse duration, 1 h on 1 h off). Glucose tolerance tests (GTTs, 1.5 g dextrose/kg BW, i.p.) were performed after overnight fasting with the stimulators on or off (sham stimulation) in randomized order separated by 3–4 days. Overnight VNS did not alter mean levels of blood pressure or heart rate, but increased fasted blood glucose levels (140 ± 13 mg/dL vs. 109 ± 8 mg/dL, P < 0.05). The area under the blood glucose concentration curves of the GTTs was larger during VNS than sham stimulation (3499 ± 211 mg/dL*h vs. 1810 ± 234 mg/dL*h, P < 0.05). One hour into the GTTs, the serum insulin concentrations had decreased during VNS (−0.57 ± 0.25 ng/mL, P < 0.05) and increased during sham stimulation (+0.71 ± 0.15 ng/mL, P < 0.05) compared to the fasted baseline levels. These results demonstrate that chronic cervical VNS elevates fasted blood glucose levels and impairs glucose tolerance likely through inhibition of glucose‐induced insulin release in conscious rats. It remains to be determined if patients treated with VNS are at greater risk of developing glucose intolerance and type 2 diabetes.

Effects of Intraoperative Vagal Nerve Stimulation on the Gastrointestinal Microbiome in a Mouse Model of Amyotrophic Lateral Sclerosis.

The gastrointestinal microbiota (GM) plays a fundamental role in health and disease and contributes to the bidirectional signaling between the gastrointestinal system and brain. The direct line of communication between these organ systems is through the vagus nerve. Therefore, vagal nerve stimulation (VNS), a commonly used technique for multiple disorders, has potential to modulate the enteric microbiota, enabling investigation and possibly treatment of numerous neurologic disorders in which the microbiota has been linked with disease. Here we investigate the effect of VNS in a mouse model of amyotrophic lateral sclerosis (ALS). B6SJL-Tg(SOD1*G93A)dl1Gur (SOD1dl) and wildtype mice underwent ventral neck surgery to access the vagus nerve. During surgery, the experimental group received 1 h of VNS, whereas the sham group underwent 1 h of sham treatment. The third (control) group did not undergo any surgical manipulation. Fecal samples were collected before surgery and at 8 d after the initial collection. Microbial DNA was sequenced to determine the GM profiles at both time points. GM profiles did not differ between genotypes at either the initial or end point. In addition, VNS did not alter GM populations, according to the parameters chosen in this study, indicating that this short intraoperative treatment is safe and has no lasting effects on the GM. Future studies are warranted to determine whether different stimulation parameters or chronic use of VNS affect GM profiles.

Chronic vagal nerve stimulation exerts additional beneficial effects on the beta-blocker-treated failing heart.

Vagal nerve stimulation (VNS) induces bradycardia in chronic heart failure (CHF). We hypothesized that beta-blocker would cover the beneficial effects of VNS on CHF if the anti-beta-adrenergic effect was the main VNS effect. This study investigated the effects of VNS on cardiac remodeling in rats with CHF treated with metoprolol. Two weeks after myocardial infarction, surviving rats were randomly assigned to groups of sham stimulation (SS), sham stimulation with metoprolol (SSM), or VNS with metoprolol (VSM). Compared to the SS group, heart rate was significantly reduced in the SSM and VSM groups. Hemodynamic assessments showed that VSM rats maintained better cardiac pump function and presented higher cardiac index and lower heart weight than SSM rats. VSM was also associated with lower plasma brain natriuretic peptide and norepinephrine levels than SSM. VSM but not SSM improved the 50-day survival rate compared with the SS group. The results suggest that VNS may exert its beneficial effects on the failing heart independently of its anti-beta-adrenergic mechanism.

Medial septal cholinergic mediation of hippocampal theta rhythm induced by vagal nerve stimulation.

BackgroundElectrical vagal nerve stimulation (VNS) has been used for years to treat patients with drug-resistant epilepsy. This technique also remains under investigation as a specific treatment of patients with Alzheimer’s disease. Recently we discovered that VNS induced hippocampal formation (HPC) type II theta rhythm, which is involved in memory consolidation. In the present study, we have extended our previous observation and addressed the neuronal substrate and pharmacological profile of HPC type II theta rhythm induced by VNS in anesthetized rats.MethodsMale Wistar rats were implanted with a VNS cuff electrode around the left vagus nerve, a tungsten microelectrode for recording the HPC field activity, and a medial septal (MS) cannula for the injection of a local anesthetic, procaine, and muscarinic agents. A direct, brief effect of VNS on the HPC field potential was evaluated before and after medial-septal drug injection.ResultsMedial septal injection of local anesthetic, procaine, reversibly abolished VNS-induced HPC theta rhythm. With the use of cholinergic muscarinic agonist and antagonists, we demonstrated that medial septal M1 receptors are involved in the mediation of the VNS effect on HPC theta field potential.ConclusionThe MS cholinergic M1 receptor mechanism integrates not only central inputs from the brainstem synchronizing pathway, which underlies the production of HPC type II theta rhythm, but also the input from the vagal afferents in the brain stem.

Bioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms.

The gastrointestinal tract has extensive, surgically accessible nerve connections with the central nervous system. This provides the opportunity to exploit rapidly advancing methods of nerve stimulation to treat gastrointestinal disorders. Bioelectric neuromodulation technology has considerably advanced in the past decade, but sacral nerve stimulation for faecal incontinence currently remains the only neuromodulation protocol in general use for a gastrointestinal disorder. Treatment of other conditions, such as IBD, obesity, nausea and gastroparesis, has had variable success. That nerves modulate inflammation in the intestine is well established, but the anti-inflammatory effects of vagal nerve stimulation have only recently been discovered, and positive effects of this approach were seen in only some patients with Crohn's disease in a single trial. Pulses of high-frequency current applied to the vagus nerve have been used to block signalling from the stomach to the brain to reduce appetite with variable outcomes. Bioelectric neuromodulation has also been investigated for postoperative ileus, gastroparesis symptoms and constipation in animal models and some clinical trials. The clinical success of this bioelectric neuromodulation therapy might be enhanced through better knowledge of the targeted nerve pathways and their physiological and pathophysiological roles, optimizing stimulation protocols and determining which patients benefit most from this therapy.

Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke

Background and Purpose- We assessed safety, feasibility, and potential effects of vagus nerve stimulation (VNS) paired with rehabilitation for improving arm function after chronic stroke. Methods- We performed a randomized, multisite, double-blinded, sham-controlled pilot study. All participants were implanted with a VNS device and received 6-week in-clinic rehabilitation followed by a home exercise program. Randomization was to active VNS (n=8) or control VNS (n=9) paired with rehabilitation. Outcomes were assessed at days 1, 30, and 90 post-completion of in-clinic therapy. Results- All participants completed the course of therapy. There were 3 serious adverse events related to surgery. Average FMA-UE scores increased 7.6 with active VNS and 5.3 points with control at day 1 post-in-clinic therapy (difference, 2.3 points; CI, -1.8 to 6.4; P=0.20). At day 90, mean scores increased 9.5 points from baseline with active VNS, and the control scores improved by 3.8 (difference, 5.7 points; CI, -1.4 to 11.5; P=0.055). The clinically meaningful response rate of FMA-UE at day 90 was 88% with active VNS and 33% with control VNS ( P<0.05). Conclusions- VNS paired with rehabilitation was acceptably safe and feasible in participants with upper limb motor deficit after chronic ischemic stroke. A pivotal study of this therapy is justified. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02243020.

Effect of Electrical Vagus Nerve Stimulation on Cerebral Blood Flow and Neurological Outcome in Asphyxial Cardiac Arrest Model of Rats.

Vagus nerve stimulation (VNS) during post-resuscitation may increase recovery of cerebral blood flow (CBF) and reduce neurological injury. This study was designed to investigate the effect of electrical VNS on neurological outcomes following cardiac arrest (CA). Male Sprague-Dawley rats (n = 48) were subjected to the asphyxial CA model and blindly allocated to the VN isolation (CA + VN isolation) or VNS group (CA + VNS group). Cardiopulmonary resuscitation was initiated 450s after pulseless electrical arrest, and the left cervical vagus nerve was electrically stimulated (0.05mA, 1Hz) for 3h in the CA + VNS group. The neurological deficit score (NDS) and overall performance category (OPC) were assessed at 24h after resuscitation, and histological injury of the hippocampus was evaluated. Independent experiments were performed to evaluate the effect of VNS on global cortical CBF after resuscitation using laser speckle Doppler imaging through a thinned skull window from pre-arrest to 6h after resuscitation. The baseline characteristics were not significantly different between the two groups. The NDS was significantly higher, and the OPC was substantially lower in the CA + VNS group (p = 0.022 and p = 0.049, respectively) supported by decrease in histological injury of the hippocampal CA1 region. CBF in the early period of post-return of spontaneous circulation (ROSC) was significantly higher in the CA + VNS group (p < 0.05 at post-ROSC 2h and 4h), and 4-hydroxynonenal was significantly lower in the CA + VNS group (p = 0.026). VNS improved cerebral perfusion and neurological outcomes at 24h after ROSC in an asphyxial CA model of rats.

PND158 - CHANGES IN SLEEP PATTERNS AFTER VAGUS NERVE STIMULATION, DEEP BRAIN STIMULATION OR EPILEPSY SURGERY: SYSTEMATIC REVIEW OF THE LITERATURE

In patients with epilepsy, multiple factors such as ictal frequency, interictal activity and anticonvulsant therapy affect sleep architecture and quality. Daytime somnolence is the most common complaint of patients with epilepsy. An increase in obstructive sleep apnea/hypopnea syndrome has been documented in patients with refractory epilepsy, associated with a decline in the quality of life. We wanted to review of the literature on the effects of three invasive procedures used in certain cases of refractory epilepsy: vagus nerve stimulation (VNS), deep brain stimulation (DBS) and epilepsy surgery, in subjective and objective sleep parameters. We performed a literature search in all the main medical databases: Medline, Embase, Cochrane, DARE and LILACS, looking for studies that evaluated the effects of VNS, DBS or epilepsy surgery on sleep parameters. In all, 36 studies, coming from 11 countries, including reviews, cohort studies, case series and case reports were included. VNS seems to induce sleep apnea, depending on stimulation variables. This condition can be reverted modifying these settings. Surgical procedures for epilepsy has been associated with an improvement in objective and subjective sleep parameters, that depend on the success of the procedure evaluated through ictal frequency control. There is evidence that non-pharmacologic treatment of epilepsy has different effects on sleep patterns. It is advisable to include objective and subjective sleep parameters in the initial evaluation and follow-up of patients considered for invasive procedures for epilepsy control, especially with VNS, due to the risk of sleep apnea. Most information comes from observational studies, with small sample sizes. More high quality studies are needed.

Vagus Nerve Stimulation Attenuates Cerebral Microinfarct and Colitis-induced Cerebral Microinfarct Aggravation in Mice.

Cerebral cortical microinfarct (CMI) is common in patients with dementia and cognitive decline. Emerging studies reported that intestinal dysfunction influenced the outcome of ischemic stroke and that vagus nerve stimulation (VNS) protected against ischemic stroke. However, the effects of intestinal dysfunction and VNS on CMI are not clear. Therefore, we examined the influence of colitis and VNS on CMI and the mechanisms of VNS attenuating CMI in mice with colitis. CMI was induced using a two-photon laser. Colitis was induced using oral dextran sodium sulfate (DSS). The cervical vagus nerve was stimulated using a constant current. In vivo blood-brain barrier (BBB) permeability was evaluated using two-photon imaging. Infarct volume, microglial and astrocyte activation, oxidative stress and proinflammatory cytokine levels were assessed using immunofluorescent and immunohistochemical staining. The BBB permeability, infarct volume, activation of microglia and astrocytes and oxidative stress increased significantly in mice with colitis and CMI compared to those in mice with CMI. However, these processes were reduced in CMI mice when VNS was performed. Brain lesions in mice with colitis and CMI were significantly ameliorated when VNS was performed during the acute phase of colitis. Our study demonstrated that VNS alleviated CMI and this neuroprotection was associated with the suppression of BBB permeability, neuroinflammation and oxidative stress. Also, our results indicated that VNS reduced colitis-induced microstroke aggravation.

Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

BackgroundExposure-based therapies are used to treat a variety of trauma- and anxiety-related disorders by generating successful extinction following cue exposure during treatment. The development of adjuvant strategies that accelerate extinction learning, improve tolerability, and increase efficiency of treatment could increase the efficacy of exposure-based therapies. Vagus nerve stimulation (VNS) paired with exposure can enhance fear extinction, in rat models of psychiatric disorders, and chronic administration of VNS reduces anxiety in rats and humans. Objective: We tested whether VNS, like other cognitive enhancers, could produce generalization of extinction for stimuli that are not presented during the extinction sessions, but are associated with the fear event. MethodsMale Sprague Dawley rats underwent auditory fear conditioning with two easily discriminable auditory stimuli. Following fear conditioning, extinction training consisted of exposure to only one of the conditioned sounds. Half of the rats received VNS and half received sham stimulation during with sound presentations. VNS effects on anxiety were examined in a separate study where VNS was administered prior to testing on the elevated plus maze. ResultsSham stimulated rats given 20 presentations of a conditioned stimulus (CS) during the extinction session showed performance that was matched to VNS-treated rats given only 4 presentations of the CS. Despite comparable levels of freezing to the presented CS, only the VNS-treated rats showed a significant decrease in freezing to the CS that was not presented. VNS-induced generalization of extinction was observed only when the two sounds were paired with footshock within the same fear conditioning session; VNS did not promote generalization of extinction when the two sounds were conditioned on different days or in different contexts. On the anxiety test, VNS administration significantly increased time spent in the open arms of the elevated plus maze. ConclusionThese results provide evidence that VNS can promote generalization of extinction to other stimuli associated with a specific fear experience. Furthermore, non-contingent VNS appears to reduce anxiety. The ability to generalize extinction and reduce anxiety makes VNS a potential candidate for use as an adjunctive strategy to improve the efficacy and tolerability of exposure-based therapies.

Vagus nerve stimulation as a tool for enhancing extinction in exposure-based therapies.

Emotionally traumatic experiences can lead to maladaptive memories that are enduring and intrusive. The goal of exposure-based therapies is to extinguish conditioned fears through repeated, unreinforced exposures to reminders of traumatic events. The extinction of conditioned fear depends upon the consolidation of new memories made during exposure to reminders. An impairment in extinction recall, observed in certain patient populations, can interfere with progress in exposure-based therapies, and the drive to avoid thoughts and reminders of the trauma can undermine compliance and increase dropout rate. Effective adjuncts to exposure-based therapies should improve the consolidation and maintenance of the extinction memory or improve the tolerability of the therapy. Under stressful conditions, the vagus nerve responds to elevations in epinephrine and signals the brain to facilitate the storage of new memories while, as part of the parasympathetic nervous system, it slows the sympathetic response. Here, we review studies relevant to fear extinction, describing the anatomical and functional characteristics of the vagus nerve and mechanisms of vagus nerve stimulation (VNS)-induced memory enhancement and plasticity. We propose that stimulation of the left cervical vagus nerve during exposure to conditioned cues signals the brain to store new memories just as epinephrine or emotional arousal would do, but bypasses the peripheral sympathetic "fight-or-flight" response. In support of this hypothesis, we have found that VNS accelerates extinction and prevents reinstatement of conditioned fear in rats. Finally, we propose future studies targeting the optimization of stimulation parameters and the search for biomarkers of VNS effectiveness that may improve exposure therapy outcomes.

Atrial GIRK Channels Mediate the Effects of Vagus Nerve Stimulation on Heart Rate Dynamics and Arrhythmogenesis.

Diminished parasympathetic influence is central to the pathogenesis of cardiovascular diseases, including heart failure and hypertension. Stimulation of the vagus nerve has shown promise in treating cardiovascular disease, prompting renewed interest in understanding the signaling pathway(s) that mediate the vagal influence on cardiac physiology. Here, we evaluated the contribution of G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels to the effect of vagus nerve stimulation (VNS) on heart rate (HR), HR variability (HRV), and arrhythmogenesis in anesthetized mice. As parasympathetic fibers innervate both atria and ventricle, and GIRK channels contribute to the cholinergic impact on atrial and ventricular myocytes, we collected in vivo electrocardiogram recordings from mice lacking either atrial or ventricular GIRK channels, during VNS. VNS decreased HR and increased HRV in control mice, in a muscarinic receptor-dependent manner. This effect was preserved in mice lacking ventricular GIRK channels, but was nearly completely absent in mice lacking GIRK channels in the atria. In addition, atrial-specific ablation of GIRK channels conferred resistance to arrhythmic episodes induced by VNS. These data indicate that atrial GIRK channels are the primary mediators of the impact of VNS on HR, HRV, and arrhythmogenesis in the anesthetized mouse.