Comparisons of electrophysiological and psychophysical fitting methods for cochlear implants.

OBJECTIVE: This study compared two different versions of an electrophysiology-based software-guided cochlear implant fitting method with a procedure employing standard clinical software. The two versions used electrically evoked compound action potential (ECAP) thresholds for either five or all twenty-two electrodes to determine sound processor stimulation level profiles. Objective and subjective performance results were compared between software-guided and clinical fittings. DESIGN: Prospective, double-blind, single-subject repeated-measures with permuted ABCA sequences. STUDY SAMPLE: 48 post linguistically deafened adults with ≤15 years of severe-to-profound deafness who were newly unilaterally implanted with a Nucleus device. RESULTS: Speech recognition in noise and quiet was not significantly different between software- guided and standard methods, but there was a visit/learning-effect. However, the 5-electrode method gave scores on the SSQ speech subscale 0.5 points lower than the standard method. Clinicians judged usability for all methods as acceptable, as did subjects for comfort. Analysis of stimulation levels and ECAP thresholds suggested that the 5-electrode method could be refined. CONCLUSIONS: Speech recognition was not inferior using either version of the electrophysiology-based software-guided fitting method compared with the standard method. Subject-reported speech perception was slightly inferior with the five-electrode method. Software-guided methods saved about 10 min of clinician's time versus standard fittings.

Gene Electrotransfer via Conductivity-Clamped Electric Field Focusing Pivots Sensori-Motor DNA Therapeutics: "A Spoonful of Sugar Helps the Medicine Go Down".

Viral vectors and lipofection-based gene therapies have dispersion-dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close-field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of "naked" plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near-field conductivity ("conductivity-clamping"-CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic-ready bionics-derived CC-GET device achieved neurotrophin-encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics-based hearing. The performance of CC-GET is evaluated in the brain, an organ problematic for pulsed electric field-based plasmid DNA delivery, due to high required currents causing Joule-heating and damaging electroporation. Here CC-GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red-shifted channelrhodopsin and a genetically-encoded Ca2+ sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.

Neurotrophin gene augmentation by electrotransfer to improve cochlear implant hearing outcomes.

This Review outlines the development of DNA-based therapeutics for treatment of hearing loss, and in particular, considers the potential to utilize the properties of recombinant neurotrophins to improve cochlear auditory (spiral ganglion) neuron survival and repair. This potential to reduce spiral ganglion neuron death and indeed re-grow the auditory nerve fibres has been the subject of considerable pre-clinical evaluation over decades with the view of improving the neural interface with cochlear implants. This provides the context for discussion about the development of a novel means of using cochlear implant electrode arrays for gene electrotransfer. Mesenchymal cells which line the cochlear perilymphatic compartment can be selectively transfected with (naked) plasmid DNA using array - based gene electrotransfer, termed 'close-field electroporation'. This technology is able to drive expression of brain derived neurotrophic factor (BDNF) in the deafened guinea pig model, causing re-growth of the spiral ganglion peripheral neurites towards the mesenchymla cells, and hence into close proximity with cochlear implant electrodes within scala tympani. This was associated with functional enhancement of the cochlear implant neural interface (lower neural recruitment thresholds and expanded dynamic range, measured using electrically - evoked auditory brainstem responses). The basis for the efficiency of close-field electroporation arises from the compression of the electric field in proximity to the ganged cochlear implant electrodes. The regions close to the array with highest field strength corresponded closely to the distribution of bioreporter cells (adherent human embryonic kidney (HEK293)) expressing green fluorescent reporter protein (GFP) following gene electrotransfer. The optimization of the gene electrotransfer parameters using this cell-based model correlated closely with in vitro and in vivo cochlear gene delivery outcomes. The migration of the cochlear implant electrode array-based gene electrotransfer platform towards a clinical trial for neurotrophin-based enhancement of cochlear implants is supported by availability of a novel regulatory compliant mini-plasmid DNA backbone (pFAR4; plasmid Free of Antibiotic Resistance v.4) which could be used to package a 'humanized' neurotrophin expression cassette. A reporter cassette packaged into pFAR4 produced prominent GFP expression in the guinea pig basal turn perilymphatic scalae. More broadly, close-field gene electrotransfer may lend itself to a spectrum of potential DNA therapeutics applications benefitting from titratable, localised, delivery of naked DNA, for gene augmentation, targeted gene regulation, or gene substitution strategies.

Sound localization with bilateral cochlear implants in noise: how much do head movements contribute to localization?

Bilateral cochlear implant (CI) users encounter difficulties in localizing sound sources in everyday environments, especially in the presence of background noise and reverberation. They tend to show large directional errors and front-back confusions compared to normal hearing (NH) subjects in the same conditions. In this study, the ability of bilateral CI users to use head movements to improve sound source localization was evaluated. Speech sentences of 0.5, 2, and 4.5 seconds were presented in noise to the listeners in conditions with and without head movements. The results show that for middle and long signal durations, the CI users could significantly reduce the number of front-back confusions. The angular accuracy, however, did not improve. Analysis of head trajectories showed that the CI users had great difficulties in moving their head towards the position of the source, whereas the NH listeners targeted the source loudspeaker correctly.

Neurophysiological evidence of impaired musical sound perception in cochlear-implant users.

OBJECTIVE: Music perception with a cochlear implant (CI) can be unsatisfactory because current-day implants are primarily designed to enable speech discrimination. The present study aimed at evaluating electrophysiological correlates of musical sound perception in CI users to help achieve the long-term goal of improved restoration of hearing in those individuals. METHODS: Auditory discrimination accuracy in adult CI users (n=12) and matched normal-hearing controls (n=12) was measured by behavioral discrimination tasks and mismatch negativity (MMN) recordings. Discrimination profiles were obtained by using a set of clarinet sounds (original/vocoded) varying along different acoustic dimensions (frequency/intensity/duration) and deviation magnitudes (four levels). RESULTS: Behavioral results and MMN recordings revealed reduced auditory discrimination accuracy in CI users. An inverse relationship was found between MMN amplitudes and duration of profound deafness. CONCLUSIONS: CI users have difficulties in discriminating small changes in the acoustic properties of musical sounds. The recently developed multi-feature MMN paradigm (Pakarinen et al., 2007) can be used to objectively evaluate discrimination abilities of CI users for musical sounds. SIGNIFICANCE: Measuring auditory discrimination functions by means of a multi-feature MMN paradigm could be of substantial clinical value by providing a comprehensive profile of the extent of restored hearing in CI users.

Neural adaptation and the ECAP response threshold: a pilot study.

The electrically evoked compound action potential (ECAP) amplitude resulting from a train of pulses of finite duration (100 ms or 200 ms) was found to vary inversely to the stimulation rate (pulse rate), corroborating well with neural adaptation results from a previous study (Dillier et al., 2005). Amplitude growth functions based on these adapted responses yield thresholds (TNRT) that increase with increasing pulse rate, contrary to behavioural thresholds, which are known to vary inversely with the stimulation rate. Adaptation effects are therefore a confounding factor that must be accounted for when attempting to compare behavioural and objective measures.