High-frequency burst vagal nerve simulation therapy in a natural primate model of genetic generalized epilepsy.

PURPOSE: Since the approval of Vagal Nerve Stimulation (VNS) Therapy for medically refractory focal epilepsies in 1997, it has been also reported to be effective for a wide range of generalized seizures types and epilepsy syndromes. Instead of conventional VNS Therapy delivered at 20-30Hz signal frequencies, this study evaluates efficacy and tolerability of high-frequency burst VNS in a natural animal model for genetic generalized epilepsy (GGE), the epileptic baboon. METHODS: Two female baboons (B1 P.h. Hamadryas and B2 P.h. Anubis x Cynocephalus) were selected because of frequently witnessed generalized tonic-clonic seizures (GTCS) for VNS implantation. High-frequency burst VNS Therapy was initiated after a 4-5 week baseline; different VNS settings (0.25, 2 or 2.5mA, 300Hz, 4 vs 7 pulses, 0.5-2.5s interburst interval, and intermittent stimulation for 1-2 vs for 24h per day) were tested over the subsequent 19 weeks, which included a 4-6 week wash-out period. GTCS frequencies were quantified for each setting, while seizure duration and postictal recovery times were compared to baseline. Scalp EEG studies were performed at almost every setting, including intermittent light stimulation (ILS) to evaluate photosensitivity. Pre-ILS ictal and interictal discharge rates, as well as ILS responses were compared between trials. The Novel Object test was used to assess potential treatment effects on behavior. RESULTS: High-frequency burst VNS Therapy reduced GTCS frequencies at all treatment settings in both baboons, except when output currents were reduced (0.25mA) or intermittent stimulation was restricted (to 1-2h/day). Seizure duration and postictal recovery times were unchanged. Scalp EEG studies did not demonstrate treatment-related decrease of ictal or interictal epileptic discharges or photosensitivity, but continuous treatment for 120-180s during ILS appeared to reduce photoparoxysmal responses. High-frequency burst VNS Therapy was well-tolerated by both baboons, without cardiac or behavioral changes. Repetitive muscle contractions involving the neck and left shoulder girdle were observed intermittently, most commonly at 0.5 interburst intervals, but these were transient, resolving with a few cycles of stimulation and not noted in wakefulness. CONCLUSIONS: This preclinical pilot study demonstrates efficacy and tolerability of high-frequency burst VNS Therapy in the baboon model of GGE. The muscle contractions may be due to aberrant propagation of the stimulus along the vagal nerve or to the ansa cervicalis, but can be reduced by minimal adjustment of current output or stimulus duration.

Application of a computational model of vagus nerve stimulation.

OBJECTIVES: The most widely used and studied neurostimulation procedure for medically refractory epilepsy is vagus nerve stimulation (VNS) Therapy. The goal of this study was to develop a computational model for improved understanding of the anatomy and neurophysiology of the vagus nerve as it pertains to the principles of electrical stimulation, aiming to provide clinicians with a systematic and rational understanding of VNS Therapy. MATERIALS AND METHODS: Computational modeling allows the study of electrical stimulation of peripheral nerves. We used finite element electric field models of the vagus nerve with VNS Therapy electrodes to calculate the voltage field for several output currents and studied the effects of two programmable parameters (output current and pulse width) on optimal fiber activation. RESULTS: The mathematical models correlated well with strength-duration curves constructed from actual patient data. In addition, digital constructs of chronic versus acute implant models demonstrated that at a given pulse width and current combination, presence of a 110-µm fibrotic tissue can decrease fiber activation by 50%. Based on our findings, a range of output current settings between 0.75 and 1.75 mA with pulse width settings of 250 or 500 µs may result in optimal stimulation. CONCLUSIONS: The modeling illustrates how to achieve full or nearly full activation of the myelinated fibers of the vagus nerve through output current and pulse width settings. This knowledge will enable clinicians to apply these principles for optimal vagus nerve activation and proceed to adjust duty cycle and frequency to achieve effectiveness.