Vagus Nerve Stimulation Intensity Research Articles

Neural mechanisms responsible for vagus nerve stimulation-dependent enhancement of somatosensory recovery

Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) combined with tactile rehabilitation has emerged as a potential approach to enhance recovery of somatosensation. In order to maximize the effectiveness of VNS therapy and promote translation to clinical implementation, we sought to optimize the stimulation paradigm and identify neural mechanisms that underlie VNS-dependent recovery. To do so, we characterized the effect of tactile rehabilitation combined with VNS across a range of stimulation intensities on recovery of somatosensory function in a rat model of chronic sensory loss in the forelimb. Consistent with previous studies in other applications, we find that moderate intensity VNS yields the most effective restoration of somatosensation, and both lower and higher VNS intensities fail to enhance recovery compared to rehabilitation without VNS. We next used the optimized, moderate intensity to evaluate the mechanisms that underlie recovery. We find that moderate intensity VNS enhances transcription of Arc, a canonical mediator of synaptic plasticity, in the cortex, and that transcript levels were correlated with the degree of somatosensory recovery. Moreover, we observe that blocking plasticity by depleting acetylcholine in the cortex prevents the VNS-dependent enhancement of somatosensory recovery. Collectively, these findings identify neural mechanisms that subserve VNS-dependent somatosensation recovery and provide a basis for selecting optimal stimulation parameters in order to facilitate translation of this potential intervention.

Optimized microburst VNS elicits fMRI responses beyond thalamic-specific response from standard VNS.

In parallel to standard vagus nerve stimulation (VNS), microburst stimulation delivery has been developed. We evaluated the fMRI-related signal changes associated with standard and optimized microburst stimulation in a proof-of-concept study (NCT03446664). Twenty-nine drug-resistant epilepsy patients were prospectively implanted with VNS. Three 3T fMRI scans were collected 2 weeks postimplantation. The maximum tolerated VNS intensity was determined prior to each scan starting at 0.125 mA with 0.125 mA increments. FMRI scans were block-design with alternating 30 sec stimulation [ON] and 30 sec no stimulation [OFF]: Scan 1 utilized standard VNS and Scan 3 optimized microburst parameters to determine target settings. Semi-automated on-site fMRI data processing utilized ON-OFF block modeling to determine VNS-related fMRI activation per stimulation setting. Anatomical thalamic mask was used to derive highest mean thalamic t-value for determination of microburst stimulation parameters. Paired t-tests corrected at P < 0.05 examined differences in fMRI responses to each stimulation type. Standard and microburst stimulation intensities at Scans 1 and 3 were similar (P = 0.16). Thalamic fMRI responses were obtained in 28 participants (19 with focal; 9 with generalized seizures). Group activation maps showed standard VNS elicited thalamic activation while optimized microburst VNS showed widespread activation patterns including thalamus. Comparison of stimulation types revealed significantly greater cerebellar, midbrain, and parietal fMRI signal changes in microburst compared to standard VNS. These differences were not associated with seizure responses. While standard and optimized microburst VNS elicited thalamic activation, microburst also engaged other brain regions. Relationship between these fMRI activation patterns and clinical response warrants further investigation. The study was registered with clinicaltrials.gov (NCT03446664).

Characterization of Vagus Nerve Stimulation (VNS) Dose-Dependent Effects on EEG Power Spectrum and Synchronization.

This study investigates the dose-dependent EEG effects of Vagus Nerve Stimulation (VNS) in patients with drug-resistant epilepsy. This research examines how varying VNS intensities impacts EEG power spectrum and synchronization in a cohort of 28 patients. Patients were categorized into responders, partial-responders, and non-responders based on seizure frequency reduction. The methods involved EEG recordings at incremental VNS intensities, followed by spectral and synchronization analysis. The results reveal significant changes in EEG power, particularly in the delta and beta bands across different intensities. Notably, responders exhibited distinct EEG changes compared to non-responders. Our study has found that VNS intensity significantly influences EEG power topographic allocation and brain desynchronization, suggesting the potential use of acute dose-dependent effects to personalized VNS therapy in the treatment of epilepsy. The findings underscore the importance of individualized VNS dosing for optimizing therapeutic outcomes and highlight the use of EEG metrics as an effective tool for monitoring and adjusting VNS parameters. These insights offer a new avenue for developing individualized VNS therapy strategies, enhancing treatment efficacy in epilepsy.

Effects of vagus nerve stimulation on the quality of sleep and sleep apnea in patients with drug-resistant epilepsy: A systematic review.

The objective was to systematically evaluate the current evidence surrounding the effect of vagus nerve stimulation (VNS) on quality of sleep and obstructive sleep apnea (OSA) among patients with epilepsy. A literature search was conducted using the Embase and MEDLINE databases. Studies were included if they involved patients with drug-resistant epilepsy treated with VNS and used validated tools to report on quality of sleep or sleep apnea. The literature search yielded 112 citations related to VNS and sleep quality, and 82 citations related to sleep apnea. Twelve articles were included in the review, of which five measured quality of sleep among patients who underwent VNS, six studies measured sleep apnea, and one study measured both outcomes. Studies measuring quality of sleep used different methods, including sleep quality questionnaires and the percentage of sleep in each cycle. Studies also varied in patient populations, the use of control groups, and whether multiple measurements were taken for each patient. Some studies found improved sleep quality after VNS, whereas others found reductions in deep sleep stages. Additionally, mixed results in sleep quality were found when comparing patients with epilepsy who received VNS treatment versus patients with epilepsy who did not receive VNS treatment. Variables such as VNS intensity and age could potentially confound quality of sleep. Studies measuring sleep apnea consistently found increased proportions of patients diagnosed with OSA or increased sleep index scores after VNS implantation. Overall, the effect of VNS on quality of sleep remains unclear, as studies were very heterogeneous, although the effect on sleep apnea has consistently shown an increase in sleep apnea severity indices after VNS implantation. Future studies with consistent measures and discussions of confounding are required to determine the effect of VNS on quality of sleep, and the effect of VNS parameters should be further explored among patients who develop sleep apnea.

Characterization of vagus nerve stimulation-induced pupillary responses in epileptic patients

BackgroundModulation of the locus coeruleus (LC)-noradrenergic system is a key mechanism of vagus nerve stimulation (VNS). Activation of the LC produces pupil dilation, and the VNS-induced change in pupil diameter was demonstrated in animals as a possible dose-dependent biomarker for treatment titration. ObjectiveThis study aimed to characterize VNS-induced pupillary responses in epileptic patients. MethodsPupil diameter was recorded in ten epileptic patients upon four stimulation conditions: three graded levels of VNS intensity and a somatosensory control stimulation (cutaneous electrical stimulation over the left clavicle). For each block, the patients rated the intensity of stimulation on a numerical scale. We extracted the latency of the peak pupil dilation and the magnitude of the early (0–2.5 s) and late components (2.5–5 s) of the pupil dilation response (PDR). ResultsVNS elicited a peak dilation with longer latency compared to the control condition (p = 0.043). The magnitude of the early PDR was significantly correlated with the intensity of perception (p = 0.046), whereas the late PDR was not (p = 0.19). There was a significant main effect of the VNS level of intensity on the magnitude of the late PDR (p = 0.01) but not on the early PDR (p = 0.2). The relationship between late PDR magnitude and VNS intensity was best fit by a Gaussian model (inverted-U). ConclusionsThe late component of the PDR might reflect specific dose-dependent effects of VNS, as compared to control somatosensory stimulation. The inverted-U relationship of late PDR with VNS intensity might indicate the engagement of antagonist central mechanisms at high stimulation intensities.

Impact Of An Automated Titration Algorithm On Battery Longevity In An Implantable Neurostimulation System For Treatment Of Chronic Heart Failure

Background Autonomic Regulation Therapy (ART) using chronic vagus nerve stimulation (VNS) is a promising new therapy for patients with heart failure (HF) who remain symptomatic despite standard care. In the ANTHEM-HF Pilot Study, a therapeutic VNS intensity was successfully achieved in patients with HFrEF using manually-programmed VNS up-titration. In the ANTHEM-HF Pilot Study (NCT01823887), the mean stimulation parameters were 2.4 ± 0.6 mA amplitude, 5 Hz frequency, 250 µs pulse width, and 23% duty cycle. A TitrationAssist algorithm has been developed for automatically intensifying VNS in small increments to a programmable target and capable of adjustments using a hand-held programmer or magnet. While this algorithm has the potential of dramatically reducing the number and duration of clinic visits for VNS titration, the impact of implementing TitrationAssist on device longevity has not been determined. Methods Current draw was measured from 32 VITARIA pulse generators (LivaNova USA, Houston, USA) with TitrationAssist activated. Testing was performed with a 3000 Ω load at programmed stimulation settings of 250 µsec pulse width, pulse frequency of 5 or 10 Hz, output current of 2.0 or 3.0 mA, and duty cycle of 23% (nominal), 33%, and 50%. The measured data was used in a standard longevity estimate process to determine the minimum longevity reached by at least 95% of devices with 95% confidence. The design requirement for battery longevity was >5 years at 10 Hz / 2.5 mA / 23%. Results Current draw was successfully measured from all 32 pulse generators and used to calculate device longevity. Device longevity, expressed in years, is shown in the table, and exceeds the system longevity requirement. At the expected stimulation parameters of 2.0-3.0 mA amplitude, 5 Hz frequency, 250 µs pulse width, 23% duty cycle, device longevity is expected to be in the range of 7-9 years. Device longevity was not significantly affected by the activation of the TitrationAssist algorithm. Conclusions At the expected stimulation parameters, VITARIA pulse generator battery longevity was determined to be 7-9 years. This exceeds the design requirement and suggests that ART can be titrated using TitrationAssist and chronically delivered without frequent generator replacement. Autonomic Regulation Therapy (ART) using chronic vagus nerve stimulation (VNS) is a promising new therapy for patients with heart failure (HF) who remain symptomatic despite standard care. In the ANTHEM-HF Pilot Study, a therapeutic VNS intensity was successfully achieved in patients with HFrEF using manually-programmed VNS up-titration. In the ANTHEM-HF Pilot Study (NCT01823887), the mean stimulation parameters were 2.4 ± 0.6 mA amplitude, 5 Hz frequency, 250 µs pulse width, and 23% duty cycle. A TitrationAssist algorithm has been developed for automatically intensifying VNS in small increments to a programmable target and capable of adjustments using a hand-held programmer or magnet. While this algorithm has the potential of dramatically reducing the number and duration of clinic visits for VNS titration, the impact of implementing TitrationAssist on device longevity has not been determined. Current draw was measured from 32 VITARIA pulse generators (LivaNova USA, Houston, USA) with TitrationAssist activated. Testing was performed with a 3000 Ω load at programmed stimulation settings of 250 µsec pulse width, pulse frequency of 5 or 10 Hz, output current of 2.0 or 3.0 mA, and duty cycle of 23% (nominal), 33%, and 50%. The measured data was used in a standard longevity estimate process to determine the minimum longevity reached by at least 95% of devices with 95% confidence. The design requirement for battery longevity was >5 years at 10 Hz / 2.5 mA / 23%. Current draw was successfully measured from all 32 pulse generators and used to calculate device longevity. Device longevity, expressed in years, is shown in the table, and exceeds the system longevity requirement. At the expected stimulation parameters of 2.0-3.0 mA amplitude, 5 Hz frequency, 250 µs pulse width, 23% duty cycle, device longevity is expected to be in the range of 7-9 years. Device longevity was not significantly affected by the activation of the TitrationAssist algorithm. At the expected stimulation parameters, VITARIA pulse generator battery longevity was determined to be 7-9 years. This exceeds the design requirement and suggests that ART can be titrated using TitrationAssist and chronically delivered without frequent generator replacement.

Persistent Autonomic Engagement and Cardiac Control After Four or More Years of Autonomic Regulation Therapy Using Vagus Nerve Stimulation.

IntroductionAlthough heart failure (HF) outcomes have improved dramatically with the use of guideline directed medical therapy and implantable devices, the overall prognosis of patients with HF and reduced ejection fraction (HFrEF) remains poor. Autonomic Regulation Therapy (ART) using chronic vagus nerve stimulation (VNS) has been evaluated in the ANTHEM-HF study, using changes in heart rate (HR) dynamics as a biomarker of autonomic nervous system engagement and cardiac control to guide VNS titration. ART was associated with sustained improvement in cardiac function and HF symptoms in patients with HFrEF and persistent HF symptoms despite guideline-directed medical therapy (GDMT). We sought to determine whether the responsiveness of the autonomic nervous system to ART, as reflected in HR response to vagus stimulation during the VNS duty cycle, is maintained after long-term chronic VNS administration.MethodsFifteen patients with HFrEF and implanted with a VNS systems in the ANTHEM-HF study were evaluated after 4.7 ± 0.3 years (range: 4.0–5.0 years) of chronic ART. ECG electrodes were placed on each patient’s wrists, and ECG rhythm strips were recorded. Instantaneous HR time series was computed at each patient’s chronically programmed VNS intensity and during progressively increasing VNS intensity. HR during active stimulation (on-time) was compared to HR just prior to initiation of each stimulation cycle (off-time).ResultsPersistent autonomic engagement was observed in a majority of patients (11 of 15, 73%) after chronic ART for four or more years. The average magnitude of HR reduction during ART on-time in all patients was 2.4 ± 3.2 bpm at the chronically programmed VNS pulse parameter settings.ConclusionAutonomic responsiveness to VNS persists in patients with HFrEF who received chronic ART for up to 5 years as a supplement to GDMT. This suggests that the effects of ART on autonomic engagement and cardiac control remain durable over time.Clinical Trial Registration[ClinicalTrials.gov], identifier [#NCT01823887, CTRI registration #CTRI/2012/05/002681].

Therapeutic responsiveness to vagus nerve stimulation in patients receiving beta-blockade for heart failure with reduced ejection fraction

BackgroundThe effect of beta-blockade (BB) on response to vagus nerve stimulation (VNS) has not been reported in patients with heart failure and reduced ejection fraction (HFrEF). In the ANTHEM-HF Study, 60 patients received chronic cervical VNS. Background pharmacological therapy remained unchanged during the study, and VNS intensity was stable once up-titrated. Significant improvement from baseline occurred in resting 24-hour heart rate (HR), 24-hour HR variability (SDNN), left ventricular EF (LVEF), 6-minute walk distance (6MWD), and quality of life (MLWHFS) at 6 months post-titration. We evaluated whether response to VNS was related to percentage of target BB dose (PTBBD) at baseline.MethodsPatients were categorized by baseline PTBBD, then analyzed for changes from baseline in symptoms and function at 6 months after VNS titration.ResultsAll patients received BB, either PTBBD ≥ 50 % (16 patients, 27 %; group 1) or PTBBD < 50 % (44 patients, 73 %; group 2). Heart rate, systolic blood pressure, LVEF, use of ACE/ARB, and use of MRA were similar between the two groups at baseline. Six months after up-titration, VNS reduced HR and significantly improved SDNN, LVEF, 6MWD, and MLWHFS equally in both groups.ConclusionsIn the ANTHEM-HF study, VNS responsiveness appeared to be independent of the baseline BB dose administered.

Implant- and anesthesia-related factors affecting cardiopulmonary threshold intensities for vagus nerve stimulation

Objective. Vagus nerve stimulation (VNS) is typically delivered at increasing stimulus intensity until a neurological or physiological response is observed (‘threshold’) for dose calibration, preclinically and therapeutically. Factors affecting VNS thresholds have not been studied systematically. In a rodent model of VNS we measured neural and physiological responses to increasing VNS intensity, determined neurological and physiological thresholds and examined the effect of implant- and anesthesia-related factors on thresholds. Approach. In acute and chronic vagus implants (45 and 20 rats, respectively) VNS was delivered under isoflurane, ketamine-xylazine, or awake conditions. Evoked compound action potentials (CAPs) were recorded and activation of different fiber types was extracted. Elicited physiological responses were registered, including changes in heart rate (HR), breathing rate (BR), and blood pressure (BP). CAP and physiological thresholds were determined. Main results. The threshold for evoking discernable CAPs (>10 µV) (CAP threshold) is significantly lower than what elicits 5%–10% drop in heart rate (heart rate threshold, HRT) (25 µA ± 1.8 vs. 80 µA ± 5.1, respectively; mean ± SEM). Changes in BP and small changes in BR (bradypnea) occur at lowest intensities (70 µA ± 8.3), followed by HR changes (80 µA ± 5.1) and finally significant changes in BR (apnea) (310 μA ± 32.5). HRT and electrode impedance are correlated in chronic (Pearson correlation r= 0.47; p< 0.001) but not in acute implants (r = −0.34; p NS); HRT and impedance both increase with implant age (r= 0.44; p< 0.001 and r = 0.64; p < 0.001, respectively). HRT is lowest when animals are awake (200 µA ± 35.5), followed by ketamine-xylazine (640 µA ± 151.5), and isoflurane (1000 µA ± 139.5). The sequence of physiological responses with increasing VNS intensity is the same in anesthetized and awake animals. Pulsing frequency affects physiological responses but not CAPs. Significance. Implant age, electrode impedance, and type of anesthesia affect VNS thresholds and should be accounted for when calibrating stimulation dose.

Vagus nerve stimulation enhances fear extinction as an inverted-U function of stimulation intensity

Studies in rodents indicate that pairing vagus nerve stimulation (VNS) with extinction training enhances fear extinction. However, the role of stimulation parameters on the effects of VNS remains largely unknown. Identifying the optimal stimulation intensity is a critical step in clinical translation of neuromodulation-based therapies. Here, we sought to investigate the role of stimulation intensity in rats receiving VNS paired with extinction training in a rat model for Posttraumatic Stress Disorder (PTSD). Male Sprague-Dawley rats underwent single prolonged stress followed by a severe fear conditioning training and were implanted with a VNS device. After recovery, independent groups of rats were exposed to extinction training paired with sham (0 mA) or VNS at different intensities (0.4, 0.8, or 1.6 mA). VNS intensities of 0.4 mA or 0.8 mA decreased conditioned fear during extinction training compared to sham stimulation. Pairing extinction training with moderate VNS intensity of 0.8 mA produced significant reduction in conditioned fear during extinction retention when rats were tested a week after VNS-paired extinction. High intensity VNS at 1.6 mA failed to enhance extinction. These findings indicate that a narrow range of VNS intensities enhances extinction learning, and suggest that the 0.8 mA VNS intensity used in earlier rodent and human stroke studies may also be the optimal in using VNS as an adjuvant in exposure therapies for PTSD.

High intensity VNS disrupts VNS-mediated plasticity in motor cortex

Vagus nerve stimulation (VNS) paired with motor rehabilitation enhances recovery of function after neurological injury in rats and humans. This effect is ascribed to VNS-dependent facilitation of plasticity in motor networks. Previous studies document an inverted-U relationship between VNS intensity and cortical plasticity, such that moderate intensities increase plasticity, while low or high intensity VNS does not. We tested the interaction of moderate and high intensity VNS trains to probe the mechanisms that may underlie VNS-dependent plasticity. Rats performed a behavioral task where VNS was paired with jaw movement during chewing. For five days, subjects received 100 pairings of moderate intensity VNS (Standard VNS), 100 pairings alternating between moderate and high intensity VNS (Interleaved VNS), or 50 pairings of moderate intensity VNS (Short VNS) approximately every 8 s. After the final behavioral session, intracortical microstimulation (ICMS) was used to evaluate movement representations in motor cortex. 100 pairings of moderate intensity VNS enhanced motor cortex plasticity. Replacing half of moderate intensity stimulation with high intensity VNS blocked this enhancement of plasticity. Removing high intensity stimulation, leaving only 50 pairings of moderate intensity VNS, reinstated plasticity. These results demonstrate that there is a period for at least 8 s after high intensity stimulation in which moderate intensity VNS is not able to engage mechanisms required for synaptic reorganization. More importantly, this study demonstrates that changes in stimulation parameters are a critical determinant of the magnitude of plasticity and likely the efficacy of VNS-enhanced recovery.

Abstract 12955: A Novel Algorithm for Automated Titration of Autonomic Regulation Therapy for Heart Failure

Background: Autonomic Regulation Therapy (ART) using chronic vagus nerve stimulation (VNS) is a promising new therapy for patients with heart failure who remain symptomatic despite standard care. In the ANTHEM-HF Pilot Study, a therapeutic VNS intensity was successfully achieved in patients with HFrEF using manually programmed VNS up-titration. An algorithm has been developed for automatically intensifying VNS in small increments to a programmable target and capable of adjustments during up-titration process using a hand-held programmer or magnet. Methods: 6 healthy canines were implanted with an implantable pulse generator (IPG) and electrical lead for right cervical VNS. IPG programming at implant activated the TA algorithm with (1) a 1-week start delay; (2) initial stimulation intensity of 0.125 mA, 130 μsec pulse width, and 5 Hz frequency; (3) target stimulation intensity of 2.5 mA, 250 μsec pulse width, and 5 Hz frequency; and (4) trajectory to achieve the target intensity in approximately 10 weeks. Magnet placement over the IPG at scheduled intervals tested algorithm design intention to decrement VNS intensity, prolong the time to reach the target intensity, and/or temporarily inhibit VNS. Results: All animals underwent successful VNS system implantation and completed all scheduled activities. There was one transient implant-related adverse event (Horner’s Syndrome). The TA algorithm performed as designed. The targeted VNS intensity was achieved as scheduled, and automated titration was well tolerated in all animals. There were no stimulation-related adverse events. ECG monitoring demonstrated no clinically significant cardiac findings. Detailed gross necropsy and macroscopic examinations revealed vagus nerves and all major organs to be normal in all animals. Conclusion: An IPG for VNS having a programmable TA algorithm for automatically intensifying VNS to a target intensity and capable of adjustment in response to magnet applications to the IPG, was successfully tested in a preclinical study of healthy canines. The TA algorithm performed as designed, appears to be safe and could dramatically reduce burden of titration in a clinical setting.

A Novel Automated Algorithm Effectively Titrates Stimulation in an Implantable Vagus Nerve Stimulation Device

Autonomic Regulation Therapy (ART) using chronic Vagus Nerve Stimulation (VNS) is in development for patients with heart failure who remain symptomatic despite standard care. In the ANTHEM-HF Pilot Study, a therapeutic VNS intensity was successfully achieved in patients with HFrEF using manually programmed VNS up-titration. An algorithm has been developed for automatically intensifying VNS in small increments to a programmable target intensity, and capable of adjustments during the up-titration process using a hand-held programmer or magnet.

A limited range of vagus nerve stimulation intensities produce motor cortex reorganization when delivered during training

Pairing vagus nerve stimulation (VNS) with rehabilitation has emerged as a potential strategy to improve recovery after neurological injury, an effect ascribed to VNS-dependent enhancement of synaptic plasticity. Previous studies demonstrate that pairing VNS with forelimb training increases forelimb movement representations in motor cortex. However, it is not known whether VNS-dependent enhancement of plasticity is restricted to forelimb training or whether VNS paired with other movements could induce plasticity of other motor representations. We tested the hypothesis that VNS paired with orofacial movements associated with chewing during an unskilled task would drive a specific increase in jaw representation in motor cortex compared to equivalent behavioral experience without VNS. Rats performed a behavioral task in which VNS at a specified intensity between 0 and 1.2 mA was paired with chewing 200 times per day for five days. Intracortical microstimulation (ICMS) was then used to document movement representations in motor cortex. VNS paired with chewing at 0.8 mA significantly increased motor cortex jaw representation compared to equivalent behavioral training without stimulation (Bonferroni-corrected unpaired t-test, p < 0.01). Higher and lower intensities failed to alter cortical plasticity. No changes in other movement representations or total motor cortex area were observed between groups. These results demonstrate that 0.8 mA VNS paired with training drives robust plasticity specific to the paired movement, is not restricted to forelimb representations, and occurs with training on an unskilled task. This suggests that moderate intensity VNS may be a useful adjuvant to enhance plasticity and support benefits of rehabilitative therapies targeting functions beyond upper limb movement.

Efficient parameters of vagus nerve stimulation to enhance extinction learning in an extinction-resistant rat model of PTSD

Vagus nerve stimulation (VNS) has shown promise as an adjuvant treatment for posttraumatic stress disorder (PTSD), as it enhances fear extinction and reduces anxiety symptoms in multiple rat models of this condition. Yet, identification of the optimal stimulation paradigm is needed to facilitate clinical translation of this potential therapy. Using an extinction-resistant rat model of PTSD, we tested whether varying VNS intensity and duration could maximize extinction learning while minimizing the total amount of stimulation. We confirmed that sham rats failed to extinguish after a week of extinction training. Delivery of the standard LONG VNS trains (30 s) at 0.4 mA enhanced extinction and reduced anxiety but did not prevent fear return. Increasing the intensity of LONG VNS trains to 0.8 mA prevented fear return and attenuated anxiety symptoms. Interestingly, delivering 1, 4 or 16 SHORT VNS bursts (0.5 s) at 0.8 mA during each cue presentation in extinction training also enhanced extinction. LONG VNS trains or multiple SHORT VNS bursts at 0.8 mA attenuated fear renewal and reinstatement, promoted extinction generalization and reduced generalized anxiety. Delivering 16 SHORT VNS bursts also facilitated extinction in fewer trials. This study provides the first evidence that brief bursts of VNS can enhance extinction training, reduce relapse and support symptom remission using much less VNS than previous protocols. These findings suggest that VNS parameters can be adjusted in order to minimize total charge delivery and maximize therapeutic effectiveness.

Vagus Nerve Stimulation for Chronic Heart Failure: Differences in Therapy Delivery and Clinical Efficacy in ANTHEM-HF, INOVATE-HF, and NECTAR-HF

Background Vagus Nerve Stimulation (VNS) is meant to deliver Autonomic Regulation Therapy (ART) to neurological targets with sufficient neuromodulation (NM) to ameliorate chronic heart failure (CHF). VNS delivery consists of its intensity (a combination of pulse amplitude, pulse frequency, and pulse duration), polarity, duty cycle (DC; stimulation “on” time and “off” time), and mode (continuous, or intermittent and periodic). In the ANTHEM-HF Pilot Study patients with CHF and reduced ejection fraction (HFrEF), VNS intensity was up-titrated until a change in heart rate (HR) dynamics was objectively confirmed. This did not require any change in GDMT and was associated with significant improvements in LVEF, 6-minute walk distance (6MWD), Minnesota Living with HF (MLWHF) score, and HR variability. Methods Qualitative and quantitative analyses used data from peer-reviewed publications and other sources in the public domain to compare VNS delivery in ANTHEM-HF, INOVATE-HF, and NECTAR-HF. Results (Table): Up-titration of VNS intensity was attempted in all 3 studies. In contrast to ANTHEM-HF, INOVATE-HF aimed only at peripheral neural targets. VNS intensity was delivered at a lower pulse frequency, and had a variable DC as a consequence of R-wave synchronization and only intermittent, periodic stimulation. In NECTAR-HF VNS intensity was delivered at a higher pulse frequency, and this was associated with intolerable adverse off-target effects which restricted VNS up-titration. Significant improvements in EF, 6MWD, MLWHF, and SDNN occurred in ANTHEM-HF relative to the other studies. Conclusion VNS differed in ANTHEM-HF when compared to INOVATE-HF and NECTAR-HF. The neural targets, pulse frequencies for titration, and the DC for NM were different. VNS in ANTHEM-HF was clinically efficacious. The ongoing ANTHEM-HFrEF Pivotal Study uses a similar paradigm.

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

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

Varying Stimulation Parameters to Improve Cortical Plasticity Generated by VNS-tone Pairing

Pairing vagus nerve stimulation (VNS) with movements or sounds can direct robust plasticity in motor or auditory cortex, respectively. The degree of map plasticity is influenced by the intensity and pulse width of VNS, number of VNS-event pairings, and the interval between each pairing. It is likely that these parameters interact, influencing optimal implementation of VNS pairing protocols. We varied VNS intensity, number of stimulations, and inter-stimulation interval (ISI) to test for interactions among these parameters. Rats were implanted with a vagus nerve stimulating cuff and randomly assigned to one of three treatment groups to receive 20 days of VNS paired with a 9-kHz tone: (1) Fast VNS: 50 daily pairings of 400-µA VNS with a 30-s ISI; (2) Dispersed VNS: 50 daily pairings of 400-µA VNS with a 180-s ISI; and (3) Standard VNS: 300 daily pairings of 800-µA VNS with a 30-s ISI. Following 20 days of VNS-tone pairing, multi-unit recordings were conducted in primary auditory cortex (A1) and receptive field properties were analyzed. Increasing ISI (Dispersed VNS) did not lead to an enhancement of cortical plasticity. Reducing the current intensity and number of stimulations (Fast VNS) resulted in robust cortical plasticity, using 6 times fewer VNS pairings than the Standard protocol. These findings reveal an interaction between current intensity, stimulation number, and ISI and identify a novel VNS paradigm that is substantially more efficient than the previous standard paradigm.

Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control.

The evoked cardiac response to bipolar cervical vagus nerve stimulation (VNS) reflects a dynamic interaction between afferent mediated decreases in central parasympathetic drive and suppressive effects evoked by direct stimulation of parasympathetic efferent axons to the heart. The neural fulcrum is defined as the operating point, based on frequency-amplitude-pulse width, where a null heart rate response is reproducibly evoked during the on-phase of VNS. Cardiac control, based on the principal of the neural fulcrum, can be elicited from either vagus. Beta-receptor blockade does not alter the tachycardia phase to low intensity VNS, but can increase the bradycardia to higher intensity VNS. While muscarinic cholinergic blockade prevented the VNS-induced bradycardia, clinically relevant doses of ACE inhibitors, beta-blockade and the funny channel blocker ivabradine did not alter the VNS chronotropic response. While there are qualitative differences in VNS heart control between awake and anaesthetized states, the physiological expression of the neural fulcrum is maintained. Vagus nerve stimulation (VNS) is an emerging therapy for treatment of chronic heart failure and remains a standard of therapy in patients with treatment-resistant epilepsy. The objective of this work was to characterize heart rate (HR) responses (HRRs) during the active phase of chronic VNS over a wide range of stimulation parameters in order to define optimal protocols for bidirectional bioelectronic control of the heart. In normal canines, bipolar electrodes were chronically implanted on the cervical vagosympathetic trunk bilaterally with anode cephalad to cathode (n=8, 'cardiac' configuration) or with electrode positions reversed (n=8, 'epilepsy' configuration). In awake state, HRRs were determined for each combination of pulse frequency (2-20Hz), intensity (0-3.5mA) and pulse widths (130-750μs) over 14months. At low intensities and higher frequency VNS, HR increased during the VNS active phase owing to afferent modulation of parasympathetic central drive. When functional effects of afferent and efferent fibre activation were balanced, a null HRR was evoked (defined as 'neural fulcrum') during which HRR≈0. As intensity increased further, HR was reduced during the active phase of VNS. While qualitatively similar, VNS delivered in the epilepsy configuration resulted in more pronounced HR acceleration and reduced HR deceleration during VNS. At termination, under anaesthesia, transection of the vagi rostral to the stimulation site eliminated the augmenting response to VNS and enhanced the parasympathetic efferent-mediated suppressing effect on electrical and mechanical function of the heart. In conclusion, VNS activates central then peripheral aspects of the cardiac nervous system. VNS control over cardiac function is maintained during chronic therapy.

Quantitative evaluation of heartbeat interval time series using Poincaré analysis reveals distinct patterns of heart rate dynamics during cycles of vagus nerve stimulation in patients with heart failure

BackgroundOptimization of stimulation parameters is essential to maximizing therapeutic efficacy and minimizing side effects. MethodsThe ANTHEM-HF study enrolled patients with heart failure who received chronic autonomic regulation therapy (ART) with an implantable vagus nerve stimulation (VNS) system on either the right (n=30) or left side (n=29). Acute effects of continuously cycling VNS on R-R interval dynamics were evaluated using post hoc Poincaré analysis of ECG recordings collected during multiple titration sessions over an 8–12week period. During each titration session, VNS intensity associated with maximum tolerable dose was determined. Poincaré plots of R-R interval time series were created for epochs when VNS cycled from OFF to ON at varying intensity levels. ResultsVNS produced an immediate, relatively small change in beat-to-beat distribution of R-R intervals during the 14-sec ON time, which was correlated with stimulation current amplitude (r=0.85, p=0.05). During titration of right-sided stimulation, there was a strong correlation (r=0.91, p=0.01) between stimulus intensity and the Poincaré parameter of standard deviation, SD1, which is associated with high-frequency heart rate variability. The effect of VNS on instantaneous heart rate was indicated by a shift in the centroid of the beat-to-beat cloud distribution demarcated by the encircling ellipse. As anticipated, left-sided stimulation did not alter any Poincaré parameter except at high stimulation intensities (≥2mA). ConclusionQuantitative Poincaré analysis reveals a tight coupling in beat-to-beat dynamics during VNS ON cycles that is directly related to stimulation intensity, providing a useful measurement for confirming autonomic engagement.