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Hughes M.L.,Boys Town National Research Hospital | Goulson A.M.,University of Nebraska - Lincoln
Ear and Hearing

Objectives: The number of distinct pitch percepts for cochlear implant (CI) listeners is somewhat limited by the number of physical electrodes in the array. Newer-generation CIs have the capability to potentially increase this number by stimulating areas of the cochlea between the physical electrodes. Currently, this is achieved by electrically coupling adjacent electrodes or by simultaneously activating two electrodes with independent current sources (i.e., current steering). Presumably, either type of dual-electrode stimulation will generate neural excitation patterns that are intermediate to those generated by either physical electrode alone (henceforth termed virtual channel). However, it is not clear whether virtual-channel stimulation yields neural recruitment patterns with similar shapes and rates of growth as compared with each physical electrode alone. The purpose of this study was to compare basic electrically evoked compound action potential (ECAP) measures for physical electrodes and virtual channels to determine whether properties of the respective excitation patterns were similar. Design: Data were collected for 12 adult CI recipients (six Nucleus Freedom CI24RE, two Advanced Bionics HiResolution 90K, and four Advanced Bionics CII). ECAP responses were measured for a set of three adjacent physical electrodes and two corresponding intermediate virtual channels (e.g., physical electrodes 4, 5, and 6 and virtual channels 4 + 5 and 5 + 6) at three positions along the electrode array (basal, middle, and apical). Virtual channels for Nucleus subjects were produced via electrical coupling of adjacent electrode pairs (dual-electrode mode). For Advanced Bionics subjects, virtual channels were produced via simultaneous, in-phase stimulation of adjacent electrode pairs with 50% of the total current delivered to each electrode in the pair. Specific ECAP measures were as follows: (1) threshold and slope of the input/output functions, (2) amplitude for a masker-probe interval of 1500 μsecs (measure of refractory recovery), and (3) relative location of spread of excitation (SOE) functions among virtual channels and adjacent physical electrodes. Measures for virtual channels were compared with those for the flanking physical electrodes using a multivariate analysis of variance. Results: There were no statistically significant differences between physical electrodes and virtual channels for ECAP thresholds, slope of the input/output function, or refractory recovery. On average, SOE functions for the virtual channels were spatially located approximately halfway between SOE functions for the adjacent physical electrodes. Conclusions: Results from this study suggest that virtual channels produce neural recruitment patterns with properties similar to those elicited by the adjacent physical electrodes. © 2011 Lippincott Williams & Wilkins, Inc. Source

Lewis J.D.,Boys Town National Research Hospital | Goodman S.S.,University of Iowa
JARO - Journal of the Association for Research in Otolaryngology

The presence of short-latency (SL), less compressive-growing components in bandpass-filtered transient-evoked otoacoustic emission (TEOAE) waveforms may implicate contributions from cochlear regions basal to the tonotopic place. Recent empirical work suggests a region of SL generation between ∼1/5 and 1/10-octave basal to the TEOAE frequency’s tonotopic place. However, this estimate may be biased to regions closer to the tonotopic place as the TEOAE extraction technique precluded measurement of components with latencies shorter than ∼5 ms. Using a variant of the non-linear, double-evoked extraction paradigm that permitted extraction of components with latencies as early as 1 ms, the current study empirically estimated the spatial-extent of the cochlear region contributing to 2 kHz SL TEOAE components. TEOAEs were evoked during simultaneous presentation of a suppressor stimulus, in order to suppress contributions to the TEOAE from different places along the cochlear partition. Three or four different-latency components of similar frequency content (∼2 kHz) were identified for most subjects. Component latencies ranged from 1.4 to 9.6 ms; latency was predictive of the component’s growth rate and the suppressor frequency to which the component’s magnitude was most sensitive to change. As component latency decreased, growth became less compressive and suppressor-frequency sensitivity shifted to higher frequencies. The shortest-latency components were most sensitive to suppressors approximately 3/5-octave higher than their nominal frequency of 2 kHz. These results are consistent with a distributed region of generation extending to approximately 3/5-octave basal to the TEOAE frequency’s tonotopic place. The empirical estimates of TEOAE generation are similar to model-based estimates where generation of the different-latency components occurs through linear reflection from impedance discontinuities distributed across the cochlear partition. © 2014, Association for Research in Otolaryngology. Source

Cosgrove D.,Boys Town National Research Hospital
Pediatric Nephrology

We have known for some time that mutations in the genes encoding 3 of the 6 type IV collagen chains are the underlying defect responsible for both X-linked (where the COL4A5 gene is involved) and autosomal (where either COL4A3 or COL4A4 genes are involved) Alport syndrome. The result of these mutations is the absence of the sub-epithelial network of all three chains in the glomerular basement membrane (GBM), resulting, at maturity, in a type IV collagen GBM network comprising only α1(IV) and α2(IV) chains. The altered GBM functions adequately in early life. Eventually, there is onset of proteinuria associated with the classic and progressive irregular thickening, thinning, and splitting of the GBM, which culminates in end-stage renal failure. We have learned much about the molecular events associated with disease onset and progression through the study of animal models for Alport syndrome, and have identified some potential therapeutic approaches that may serve to delay the onset or slow the progression of the disease. This review focuses on where we are in our understanding of the disease, where we need to go to understand the molecular triggers that set the process in motion, and what emergent therapeutic approaches show promise for ameliorating disease progression in the clinic. © IPNA 2011. Source

Keefe D.H.,Boys Town National Research Hospital
Journal of the Acoustical Society of America

A click-evoked otoacoustic emission (CEOAE) has group delay and spread as first- and second-order temporal moments varying over frequency, and instantaneous frequency and bandwidth as first- and second-order spectral moments varying over time. Energy-smoothed moments were calculated from a CEOAE database over 0.5-15 kHz bandwidth and 0.25-20 ms duration. Group delay and instantaneous frequency were calculated without phase unwrapping using a coherence synchrony measure that accurately classified ears with hearing loss. CEOAE moment measurements were repeatable in individual ears. Group delays were similar for CEOAEs and stimulus-frequency OAEs. Group spread is a frequency-specific measure of temporal spread in an emission, related to spatial spread across tonotopic generation sites along the cochlea. In normal ears, group delay and spread increased with frequency and decreased with level. A direct measure of cochlear tuning above 4 kHz was analyzed using instantaneous frequency and bandwidth. Synchronized spontaneous OAEs were present in most ears below 4 kHz, and confounded interpretation of moments. In ears with sensorineural hearing loss, group delay and spread varied with audiometric classification and amount of hearing loss; group delay differed between older males and females. CEOAE moments reveal clinically relevant information on cochlear tuning in ears with normal and impaired hearing. © 2012 Acoustical Society of America. Source

The inhibitory effects and mechanism(s) of type IV collagen α-6 chain-derived noncollagenous domain (α6[IV]NC1 or hexastatin) on elastin-derived peptide (EDP)-activated choroidal endothelial cell migration, kinase signaling, and membrane type 1 metalloproteinase (MT1-MMP) activation are explored. Mouse choroidal endothelial cells (MCECs) were incubated in media with soluble EDPs (kappa elastin, mouse elastin, and Val-Gly-Val-Ala-Pro-Gly [VGVAPG] hexapeptide) for different time intervals with or without α6(IV)NC1. The MCECs proliferation, migration, tube formation, MT1-MMP expression, and angiogenic signaling were analyzed in cells subjected to EDP and α6(IV)NC1 treatments. The MCECs also were subjected to EDPs, and specific inhibitors for evaluation of focal adhesion kinase (FAK) and protein kinase B (Akt) phosphorylation. Kappa elastin, mouse elastin, and VGVAPG enhanced the migration, without affecting the proliferation of MCECs. The α6(IV)NC1 inhibited survival and EDP-activated migration of MCECs. The EDP-activated MCEC tube formation on matrigel also was inhibited by α6(IV)NC1. Further, EDP-activated MT1-MMP expression and FAK/phosphoinositide-3-kinase (PI-3K)/mammalian target of rapamycin (mToR)/Akt phosphorylation in MCECs, were reduced by α6(IV)NC1. The EDP-induced FAK and Akt phosphorylation was blocked by FAK- and Akt-specific inhibitors. The EDPs and α6(IV)NC1 are identified to exhibit opposing effects on MCEC angiogenic behavior and signaling. The α6(IV)NC1 inhibited cell survival, EDP-mediated migration, MT1-MMP expression and, FAK/PI-3K/mToR/Akt phosphorylation in MCECs. This work demonstrates α6(IV)NC1 as a prospective endogenous molecule for the treatment of diseases involving choroidal neovascularization in the eye. Source

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