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.

White Matter Tract Pathology in Pediatric Anoxic Brain Injury from Drowning.

BACKGROUND AND PURPOSE: Although drowning is a leading cause of mortality and morbidity in young children, the neuropathologic consequences have not been fully determined. The purpose of this article was to quantitatively characterize white matter microstructural abnormalities in pediatric anoxic brain injury from nonfatal drowning and investigate the correlation with motor function. MATERIALS AND METHODS: Whole-brain T1-weighted and diffusion-weighted MR imaging datasets were acquired in 11 children with chronic anoxic brain injury and 11 age- and sex-matched neurotypical controls (4-12 years of age). A systematic evaluation form and scoring system were created to assess motor function. Tract-Based Spatial Statistics was used to quantify between-group alterations in the diffusion tensor imaging indices of fractional anisotropy and mean diffusivity and to correlate with per-subject functional motor scores. RESULTS: Group-wise Tract-Based Spatial Statistics analyses demonstrated reduced fractional anisotropy in the bilateral posterior limbs of the internal capsule and the splenium of the corpus callosum (P < .001). Mean diffusivity was more diffusely increased, affecting the bilateral superior corona radiata, anterior and posterior limbs of the internal capsule, and external capsules (P < .001). Individual-subject fractional anisotropy and mean diffusivity values derived from the ROIs of the bilateral posterior limbs of the internal capsule strongly correlated with motor scores and demonstrated more potent between-group effects than with ROIs of the entire corticospinal tract. CONCLUSIONS: These data particularly implicate the deep white matter, predominantly the posterior limbs of the internal capsule, as targets of damage in pediatric anoxic brain injury with drowning. The substantial involvement of motor-system tracts with relative sparing elsewhere is notable. These results localize white matter pathology and inform future diagnostic and prognostic markers.

3D modeling of the total electric field induced by transcranial magnetic stimulation using the boundary element method.

Transcranial magnetic stimulation (TMS) delivers highly localized brain stimulations via non-invasive externally applied magnetic fields. This non-invasive, painless technique provides researchers and clinicians with a unique tool capable of stimulating both the central and peripheral nervous systems. However, a complete analysis of the macroscopic electric fields produced by TMS has not yet been performed. In this paper, we addressed the importance of the secondary E-field created by surface charge accumulation during TMS using the boundary element method (BEM). 3D models were developed using simple head geometries in order to test the model and compare it with measured values. The effects of tissue geometry, size and conductivity were also investigated. Finally, a realistically shaped head model was used to assess the effect of multiple surfaces on the total E-field. Secondary E-fields have the greatest impact at areas in close proximity to each tissue layer. Throughout the head, the secondary E-field magnitudes typically range from 20% to 35% of the primary E-field's magnitude. The direction of the secondary E-field was generally in opposition to the primary E-field; however, for some locations, this was not the case (i.e. going from high to low conductivity tissues). These findings show that realistically shaped head geometries are important for accurate modeling of the total E-field.

Detailed 3D models of the induced electric field of transcranial magnetic stimulation coils.

Previous models neglected contributions from current elements spanning the full geometric extent of wires in transcranial magnetic stimulation (TMS) coils. A detailed account of TMS coil wiring geometry is shown to provide significant improvements in the accuracy of electric field (E-field) models. Modeling E-field dependence based on the TMS coil's wire width, height, shape and number of turns clearly improved the fit of calculated-to-measured E-fields near the coil body. Detailed E-field models were accurate up to the surface of the coil body (within 0.5% of measured) where simple models were often inadequate (up to 32% different from measured).