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

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. INTERPRETATION: 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. CLINICAL TRIAL REGISTRATION: The study was registered with clinicaltrials.gov (NCT03446664).

Compatibility of Standard Vagus Nerve Stimulation and Investigational Microburst Vagus Nerve Stimulation Therapy with fMRI.

Vagus nerve stimulation devices are conditionally approved for MR imaging with stimulation turned off, and the requirement to modify the stimulation settings may be a barrier to scanning in some radiology practices. There is increasing interest in studying the effects of stimulation during MR imaging/fMRI. This study evaluated the safety of standard and investigational microburst vagus nerve stimulation therapies during MR imaging/fMRI. A prospective, multicenter study was conducted in patients with an investigational vagus nerve stimulation device that delivered either standard or investigational microburst vagus nerve stimulation. Thirty participants underwent sequential MR imaging and fMRI scans, encompassing 188 total hours of scan time (62.7 hours with standard vagus nerve stimulation and 125.3 hours with investigational microburst vagus nerve stimulation). No adverse events were reported with active stimulation during MR imaging or during 12 months of follow-up. Our results support the safety of standard and investigational microburst vagus nerve stimulation therapy during MR imaging and fMRI scans.

Spatially selective stimulation of the pig vagus nerve to modulate target effect versus side effect.

Electrical stimulation of the cervical vagus nerve using implanted electrodes (VNS) is FDA-approved for the treatment of drug-resistant epilepsy, treatment-resistant depression, and most recently, chronic ischemic stroke rehabilitation. However, VNS is critically limited by the unwanted stimulation of nearby neck muscles-a result of non-specific stimulation activating motor nerve fibers within the vagus. Prior studies suggested that precise placement of small epineural electrodes can modify VNS therapeutic effects, such as cardiac responses. However, it remains unclear if placement can alter the balance between intended effect and limiting side effect. We used an FDA investigational device exemption approved six-contact epineural cuff to deliver VNS in pigs and quantified how epineural electrode location impacts on- and off-target VNS activation. Detailed post-mortem histology was conducted to understand how the underlying neuroanatomy impacts observed functional responses. Here we report the discovery and characterization of clear neuroanatomy-dependent differences in threshold and saturation for responses related to both effect (change in heart rate) and side effect (neck muscle contractions). The histological and electrophysiological data were used to develop and validate subject-specific computation models of VNS, creating a well-grounded quantitative framework to optimize electrode location-specific activation of nerve fibers governing intended effect versus unwanted side effect.

Investigating the Effect of Short Term Responsive VNS Therapy on Sleep Quality Using Automatic Sleep Staging.

OBJECTIVE: The goal of this work is to objectively evaluate the effectiveness of responsive (or closed-loop) Vagus nerve stimulation (VNS) therapy in sleep quality in patients with medically refractory epilepsy. METHODS: Using quantitative features obtained from electroencephalography, we first developed a new automatic sleep-staging framework that consists of a multi-class support vector machine (SVM) classification, based on a decision tree approach. To train and evaluate the performance of the framework, we used polysomnographic data of 23 healthy subjects from the PhysioBank database where the sleep stages have been visually annotated. We then used the trained classifier to label the sleep stages using data from 22 patients with epilepsy, treated with short term responsive VNS therapy during an epilepsy-monitoring unit visit, one month after VNS implantation, and ten VNS-naïve patients with epilepsy. RESULTS: Application of multi-class SVM classifier to classify the three sleep stages of awake, light sleep + rapid eye movement, and deep sleep achieved a classification accuracy of 90%. Results of the application of this methodology to VNS-treated and VNS-naïve patients revealed that the patients treated with short term responsive VNS therapy showed significant increase in sleep efficiency, and significant decrease in seizures plus interictal epileptiform discharges and awakenings. CONCLUSION: These results indicate that VNS treatment can reduce the epileptiform activities and thus help in achieving better sleep quality for patients with epilepsy. SIGNIFICANCE: The proposed approach can be used to investigate the effect of long-term VNS therapy on sleep quality.

Automatic Vagus Nerve Stimulation Triggered by Ictal Tachycardia: Clinical Outcomes and Device Performance--The U.S. E-37 Trial.

OBJECTIVES: The Automatic Stimulation Mode (AutoStim) feature of the Model 106 Vagus Nerve Stimulation (VNS) Therapy System stimulates the left vagus nerve on detecting tachycardia. This study evaluates performance, safety of the AutoStim feature during a 3-5-day Epilepsy Monitoring Unit (EMU) stay and long- term clinical outcomes of the device stimulating in all modes. MATERIALS AND METHODS: The E-37 protocol (NCT01846741) was a prospective, unblinded, U.S. multisite study of the AspireSR(®) in subjects with drug-resistant partial onset seizures and history of ictal tachycardia. VNS Normal and Magnet Modes stimulation were present at all times except during the EMU stay. Outpatient visits at 3, 6, and 12 months tracked seizure frequency, severity, quality of life, and adverse events. RESULTS: Twenty implanted subjects (ages 21-69) experienced 89 seizures in the EMU. 28/38 (73.7%) of complex partial and secondarily generalized seizures exhibited ≥20% increase in heart rate change. 31/89 (34.8%) of seizures were treated by Automatic Stimulation on detection; 19/31 (61.3%) seizures ended during the stimulation with a median time from stimulation onset to seizure end of 35 sec. Mean duty cycle at six-months increased from 11% to 16%. At 12 months, quality of life and seizure severity scores improved, and responder rate was 50%. Common adverse events were dysphonia (n = 7), convulsion (n = 6), and oropharyngeal pain (n = 3). CONCLUSIONS: The Model 106 performed as intended in the study population, was well tolerated and associated with clinical improvement from baseline. The study design did not allow determination of which factors were responsible for improvements.

Vagus nerve stimulation therapy system: in vitro evaluation of magnetic resonance imaging-related heating and function at 1.5 and 3 tesla.

Objectives. To evaluate magnetic resonance imaging-related (MRI-related) heating for the VNS Therapy System at 1.5 and 3 tesla (T) using various device configurations and MRI conditions and to assess device function before and after MRI. Methods. The VNS Therapy System (pulse generator, Model 102; leads Models 300 and 302; Cyberonics, Inc., Houston, Tex, USA) underwent assessment of MRI-related heating at 1.5 and 3 T using different positioning configurations, leads, transmit radiofrequency (RF) coils (body and head), RF power levels, and scans on different body regions. The function of the VNS Therapy System was evaluated before and after scanning. Results. At 1.5 T using a transmit RF body coil, excessive temperature changes were associated with scans of the C-spine/shoulder (+11.5°C, complete system; +29.5°C, lead without pulse generator). The lowest temperature change occurred for the scan of the L-spine. At 1.5 T using a transmit/receive RF head coil, temperature changes did not exceed +0.2°C under the conditions studied. At 3 T using a transmit RF body coil, the highest temperature change occurred with the scan of the C-spine/shoulder (+14.5°C) with the lead configured with no strain relief loops at the vagus nerve. MRI performed using various conditions at 1.5 and 3 T produced no significant alterations in the function of the VNS Therapy System. Conclusions. MRI-related heating was characterized for a variety of scenarios, identifying unsafe as well as safe conditions. Device function was unaffected by MRI procedures at 1.5 and 3 T. By following specific conditions, safety guidelines for the VNS Therapy System may be expanded beyond those currently indicated by the manufacturer.