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UNLABELLED: A fast-growing field of neuroscience and medicine is the treatment of disease via electrical stimulation of the peripheral nervous system. Peripheral nerve stimulation delivers stimulation to nerves of the periphery where the target nerve can and is often located deep within the abdomen. Long-term preclinical animal models that demonstrate the safety and/or efficacy of electrical stimulation have predominantly used a skull mount to connect to neural interfaces. When targeting nerves of the extremities and abdomen, this mount location is less favourable due to its distance to the implant causing complications in surgery and to the longevity of the device in vivo. OBJECTIVE: Here we aimed to develop and validate a chronic magnetic percutaneous connector designed for placement on the dorsal-lumbar aspect of the spine of awake, freely moving rats. METHODS: A pedestal and external connector was developed, bench tested to assess for continuity, durability and disconnection forces, and validated in awake rats chronically implanted with an abdominal vagus nerve electrode array. The implanted pedestal and external connector were designed with custom PCBs, spring-loaded pins, magnets and biocompatible 3D printed housing. RESULTS: The magnetic coupling mechanism allowed disconnection with minimal force, was highly reliable in maintaining electrical connection in awake rats and allowed recording of electrically evoked compound action potentials after chronic implantation. CONCLUSION: In conclusion, this percutaneous connector is a useful research tool for peripheral nerve stimulation studies. SIGNIFICANCE: The connector described will allow investigation into the safety and efficacy of emerging neuromodulation therapies for the treatment of disease.

For individuals with severe to profound hearing loss resulting from irreversibly damaged hair cells, cochlear implants can be used to restore hearing by delivering electrical stimulation directly to the spiral ganglion neurons. However, current spread lowers the spatial resolution of neural activation. Since light can be easily confined, optogenetics is a technique that has the potential to improve the precision of neural activation, whereby visible light is used to stimulate neurons that are modified with light-sensitive opsins. This study compares the spread of neural activity across the inferior colliculus of the auditory midbrain during electrical and optical stimulation in the cochlea of acutely deafened mice with opsin-modified spiral ganglion neurons (H134R variant of the channelrhodopsin-2). Monopolar electrical stimulation was delivered via each of four 0.2 mm wide platinum electrode rings at 0.6 mm centre-to-centre spacing, whereas 453 nm wavelength light was delivered via each of five 0.22 × 0.27 mm micro-light emitting diodes (LEDs) at 0.52 mm centre-to-centre spacing. Channel interactions were also quantified by threshold changes during simultaneous stimulation by pairs of electrodes or micro-LEDs at different distances between the electrodes (0.6, 1.2 and 1.8 mm) or micro-LEDs (0.52, 1.04, 1.56 and 2.08 mm). The spread of activation resulting from single channel optical stimulation was approximately half that of monopolar electrical stimulation as measured at two levels of discrimination above threshold (p<0.001), whereas there was no significant difference between optical stimulation in opsin-modified deafened mice and pure tone acoustic stimulation in normal-hearing mice. During simultaneous micro-LED stimulation, there were minimal channel interactions for all micro-LED spacings tested. For neighbouring micro-LEDs/electrodes, the relative influence on threshold was 13-fold less for optical stimulation compared electrical stimulation (p<0.05). The ou

Objective. Optogenetic stimulation of the auditory nerve offers the ability to overcome the limitations of cochlear implants through spatially precise stimulation, but cannot achieve the temporal precision nor temporal fidelity required for good hearing outcomes. Auditory midbrain recordings have indicated a combined (hybrid) stimulation approach may permit improvements in the temporal precision without sacrificing spatial precision by facilitating electrical activation thresholds. However, previous research has been conducted in undeafened or acutely deafened animal models, and the impact of chronic deafness remains unclear. Our study aims to compare the temporal precision of auditory nerve responses to optogenetic, electrical, and combined stimulation in acutely and chronically deafened animals.Methods. We directly compare the temporal fidelity (measured as percentage of elicited responses) and precision (i.e. stability of response size and timing) of electrical, optogenetic, and hybrid stimulation (varying sub-threshold or supra-threshold optogenetic power levels combined with electrical stimuli) through compound action potential and single-unit recordings of the auditory nerve in transgenic mice expressing the opsin ChR2-H134R in auditory neurons. Recordings were conducted immediately or 2-3 weeks following aminoglycoside deafening when there was evidence of auditory nerve degeneration.Main results. Results showed that responses to electrical stimulation had significantly greater temporal precision than optogenetic stimulation (p< 0.001 for measures of response size and timing). This temporal precision could be maintained with hybrid stimulation, but only when the optogenetic stimulation power used was below or near activation threshold and worsened with increasing optical power. Chronically deafened mice showed poorer facilitation of electrical activation thresholds with concurrent optogenetic stimulation than acutely deafened mice. Additionally, responses in c

Vagus nerve stimulation is emerging as a promising treatment for type 2 diabetes. Here, we evaluated the ability of stimulation of the vagus nerve to reduce glycemia in awake, freely moving metabolically compromised rats. A model of type 2 diabetes (n = 10) was induced using a high-fat diet and low doses of streptozotocin. Stimulation of the abdominal vagus nerve was achieved by pairing 15 Hz pulses on a distal pair of electrodes with high-frequency blocking stimulation (26 kHz, 4 mA) on a proximal pair of electrodes to preferentially produce efferent conducting activity (eVNS). Stimulation was well tolerated in awake, freely moving rats. During 1 h of eVNS, glycemia decreased in 90% of subjects (-1.25 ± 1.25 mM h, p = 0.017), and 2 dB above neural threshold was established as the most effective "dose" of eVNS (p = 0.009). Following 5 weeks of implantation, eVNS was still effective, resulting in significantly decreased glycemia (-1.7 ± 0.6 mM h, p = 0.003) during 1 h of eVNS. There were no overt changes in fascicle area or signs of histopathological damage observed in implanted vagal nerve tissue following chronic implantation and stimulation. Demonstration of the biocompatibility and safety of eVNS in awake, metabolically compromised animals is a critical first step to establishing this therapy for clinical use. With further development, eVNS could be a promising novel therapy for treating type 2 diabetes.

The electrical and biological interfacial properties of invasive electrodes have a significant impact on the performance and longevity of neural recordings in the brain. In this study, we demonstrated rapid electrophoretic deposition and electrochemical reduction of graphene oxide (GO) on metal-based neural electrodes. Scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and other characterizations confirmed the existence of a uniform and effectively reduced graphene oxide coating. Electrochemically reduced graphene oxide (ErGO) coated Pt/Ir neural electrodes exhibited 15.2-fold increase in charge storage capacity (CSC) and 90% decrease in impedance with only 3.8% increase in electrode diameter. Patch clamp electrophysiology and calcium imaging of primary rat hippocampus neurons cultured on ErGO demonstrated that there was no adverse impact on the functional development of neurons. Immunostaining showed a balanced growth of excitatory and inhibitory neurons, and astrocytes. Acute recordings from the auditory cortex and chronic recordings (19 days) from the somatosensory cortex found ErGO coating improved the performance of neural electrodes in signal-to-noise ratio (SNR) and amplitude of signals. The proposed approach not only provides an in-depth evaluation of the effect of ErGO coating on neural electrodes but also widens the coating methods of commercial neural electrodes.

The expansion of criteria for cochlear implantation has resulted in increasing numbers of cochlear implant subjects having some level of residual hearing. The present study examined the effects of implantation surgery and long-term electrical stimulation on residual hearing in a partially deafened cat model. Eighteen animals were partially deafened, implanted and chronically stimulated. Implantation resulted in a pronounced loss evident 2-weeks post implantation of up to 30-40 dB at 4 & 8 kHz which was statistically significant (2-way RM ANOVA (Time, Frequency): p(Time) = 0.001; p(Frequency) < 0.001; p(Time x Frequency) < 0.001)). Chronic stimulation resulted in a significant (RM ANOVA: p(Time) = 0.030) ongoing hearing loss, with 5 animals (∼30%) exhibiting an increase in threshold of 20 dB or more. Different loss profiles were evident with peripheral and central hearing assessments suggests that changes in 'central gain' may be occurring. Despite significant loss of hair cells and spiral ganglion neurons and distinct fibrous tissue growth in the scala tympani following implantation and long-term electrical stimulation, there were no significant correlations with any histological measures and ongoing hearing loss. The partially deafened, chronically stimulated cat model provides a clinically relevant model in which to further investigate the cause of the delayed hearing loss following cochlear implant surgery and use.

Many hearing-impaired patients may significantly benefit from the Hybrid or electro-acoustic stimulation (EAS) cochlear implant (CI). However, as much as 30-55% of CI recipients lose residual hearing after implantation and the potential for associated benefits of EAS over traditional electric-only stimulation. The cause of this post-implantation hearing loss may be immediate or delayed and result from several factors, including surgical trauma, electric stimulation, and the foreign body response. Clinical and post-mortem studies have helped identify factors effecting EAS performance. Animal CI models are an essential translational tool to further investigate these pertinent issues through histopathological investigation with greater control of biological and stimulation variables as well as other unique research tools not available in clinical and post-mortem research. Additionally, animal CI models may provide useful preclinical data for potential therapeutic strategies aimed at improving EAS outcomes. Here we review the parameters required for rigorous study of mechanisms of post-implantation hearing loss, including selection of animal model, hearing loss model, age and sex considerations, surgical technique, and chronic electrical stimulation.

There is an increasing trend to provide cochlear implants for people with useful residual hearing, typically in the low frequency range (<2 kHz). These recipients typically use both electrical stimulation from their implant and acoustic stimulation that has been amplified with a hearing aid to access their residual hearing, so called electro-acoustic stimulation (EAS). However, a significant problem is the loss of residual hearing following implantation that can occur immediately following surgery or delayed over many months. One potential cause of the loss of residual hearing is the over stimulation of remaining hair cells due to the combination of an amplified acoustic input and direct electrical activation. This paper aims to test this hypothesis. Here, we have used a neonatal aminoglycoside-induced partial hearing cat model that resulted in a high frequency hearing loss (>4 kHz). Two separate cohorts of animals were implanted and received unilateral chronic electrical stimulation using clinical stimulators and speech processors over 5 months. To simulate potential over stimulation via a hearing aid, one cohort of animals were also exposed to an enhanced acoustic environment consisting of 80 dB SPL 4-talker babble presented 14 h per day. Hearing thresholds for both stimulated and unstimulated ears were measured throughout the implantation period. Cochleae were collected for histology to measure spiral ganglion neuron survival, hair cell survival and tissue response to chronic implantation and electrical stimulation. Consistent with clinical observations, cochlear implantation and stimulation resulted in an increase in threshold across the population. There was no significant effect of the enhanced acoustic environment on auditory thresholds or histological measures (hair cell survival, neuronal survival) of hearing, indicating that hair cell overstimulation was not a significant driver of loss of residual hearing.

Optical stimulation is a paradigm-shifting approach to modulating neural activity that has the potential to overcome the issue of current spread that occurs with electrical stimulation by providing focused stimuli. But optical stimulation either requires high power infrared light or genetic modification of neurons to make them responsive to lower power visible light. This work examines optical activation of auditory neurons following optogenetic modification via AAV injection in two species (mouse and guinea pig). An Anc80 viral vector was used to express the channelrhodopsin variant ChR2-H134R fused to a fluorescent reporter gene under the control of the human synapsin-1 promoter. The AAV was administered directly to the cochlea (n = 33) or posterior semi-circular canal of C57BL/6 mice (n = 4) or to guinea pig cochleae (n = 6). Light (488 nm), electrical stimuli or the combination of these (hybrid stimulation) was delivered to the cochlea via a laser-coupled optical fibre and co-located platinum wire. Activation thresholds, spread of activation and stimulus interactions were obtained from multi-unit recordings from the central nucleus of the inferior colliculus of injected mice, as well as ChR2-H134R transgenic mice (n = 4). Expression of ChR2-H134R was examined by histology. In the mouse, transduction of auditory neurons by the Anc80 viral vector was most successful when injected at a neonatal age with up to 89% of neurons transduced. Auditory neuron transductions were not successful in guinea pigs. Inferior colliculus responses to optical stimuli were detected in a cochleotopic manner in all mice with ChR2-H134R expression. There was a significant correlation between lower activation thresholds in mice and higher proportions of transduced neurons. There was no difference in spread of activation between optical stimulation and electrical stimulation provided by the light/electrical delivery system used here (optical fibre with bonded 25 µm platinum/iridium wire).

Active implantable neurological devices like deep brain stimulators have been used over the past few decades to treat movement disorders such as those in people with Parkinson's disease and more recently, in psychiatric conditions like obsessive compulsive disorder. Electrode-tissue interfaces that support safe and effective targeting of specific brain regions are critical to success of these devices. Development of directional electrodes that activate smaller volumes of brain tissue requires electrodes to operate safely with higher charge densities. Coatings such as conductive hydrogels (CHs) provide lower impedances and higher charge injection limits (CILs) than standard platinum electrodes and support safer application of smaller electrode sizes. The aim of this study was to examine the chronic in vivo performance of a new low swelling CH coating that supports higher safe charge densities than traditional platinum electrodes. A range of hydrogel blends were engineered and their swelling and electrical performance compared. Electrochemical performance and stability of high and low swelling formulations were compared during insertion into a model brain in vitro and the formulation with lower swelling characteristics was chosen for the in vivo study. CH-coated or uncoated Pt electrode arrays were implanted into the brains of 14 rats, and their electrochemical performance was tested weekly for 8 weeks. Tissue response and neural survival was assessed histologically following electrode array removal. CH coating resulted in significantly lower voltage transient impedance, higher CIL, lower electrochemical impedance spectroscopy, and higher charge storage capacity compared to uncoated Pt electrodes in vivo, and this advantage was maintained over the 8-week implantation. There was no significant difference in evoked potential thresholds, signal-to-noise ratio, tissue response or neural survival between CH-coated and uncoated Pt groups. The significant electrochemical adv

Objective.Neuromodulation of visceral nerves is being intensively studied for treating a wide range of conditions, but effective translation requires increasing the efficacy and predictability of neural interface performance. Here we use computational models of rat visceral nerve to predict how neuroanatomical variability could affect both electrical stimulation and recording with an experimental planar neural interface.Approach.We developed a hybrid computational pipeline,VisceralNerveEnsembleRecording andStimulation (ViNERS), to couple finite-element modelling of extracellular electrical fields with biophysical simulations of individual axons. Anatomical properties of fascicles and axons in rat pelvic and vagus nerves were measured or obtained from public datasets. To validate ViNERS, we simulated pelvic nerve stimulation and recording with an experimental four-electrode planar array.Main results.Axon diameters measured from pelvic nerve were used to model a population of myelinated and unmyelinated axons and simulate recordings of electrically evoked single-unit field potentials (SUFPs). Across visceral nerve fascicles of increasing size, our simulations predicted an increase in stimulation threshold and a decrease in SUFP amplitude. Simulated threshold changes were dominated by changes in perineurium thickness, which correlates with fascicle diameter. We also demonstrated that ViNERS could simulate recordings of electrically-evoked compound action potentials (ECAPs) that were qualitatively similar to pelvic nerve recording made with the array used for simulation.Significance.We introduce ViNERS as a new open-source computational tool for modelling large-scale stimulation and recording from visceral nerves. ViNERS predicts how neuroanatomical variation in rat pelvic nerve affects stimulation and recording with an experimental planar electrode array. We show ViNERS can simulate ECAPS that capture features of our recordings, but our results suggest the underlying N

Purpose: To investigate oculomotor behavior in response to dynamic stimuli in retinal implant recipients. Methods: Three suprachoroidal retinal implant recipients performed a four-alternative forced-choice motion discrimination task over six sessions longitudinally. Stimuli were a single white bar (“moving bar”) or a series of white bars (“moving grating”) sweeping left, right, up, or down across a 42′′ monitor. Performance was compared with normal video processing and scrambled video processing (randomized image-to-electrode mapping to disrupt spatiotemporal structure). Eye and head movement was monitored through-out the task. Results: Two subjects had diminished performance with scrambling, suggesting retinotopic discrimination was used in the normal condition and made smooth pursuit eye movements congruent to the moving bar stimulus direction. These two subjects also made stimulus-related eye movements resembling optokinetic reflex (OKR) for moving grating stimuli, but the movement was incongruent with stimulus direction. The third subject was less adept at the task, appeared primarily reliant on head position cues (head movements were congruent to stimulus direction), and did not exhibit retinotopic discrimination and associated eye movements. Conclusions: Our observation of smooth pursuit indicates residual functionality of corti-cal direction-selective circuits and implies a more naturalistic perception of motion than expected. A distorted OKR implies improper functionality of retinal direction-selective circuits, possibly due to retinal remodeling or the non-selective nature of the electrical stimulation. Translational Relevance: Retinal implant users can make naturalistic eye movements in response to moving stimuli, highlighting the potential for eye tracker feedback to improve perceptual localization and image stabilization in camera-based visual prosthe-ses.

Objective. Evaluate electrochemical properties, biological response, and surface characterization of a conductive hydrogel (CH) coating following chronic in vivo stimulation. Approach. Coated CH or uncoated smooth platinum (Pt) electrode arrays were implanted into the cochlea of rats and stimulated over a 5 week period with more than 57 million biphasic current pulses. Electrochemical impedance spectroscopy (EIS), charge storage capacity (CSC), charge injection limit (CIL), and voltage transient (VT) impedance were measured on the bench before and after stimulation, and in vivo during the stimulation program. Electrically-evoked auditory brainstem responses were recorded to monitor neural function. Following explant, the cochleae were examined histologically and electrodes were examined using scanning electron microscopy. Main results. CH coated electrodes demonstrated a bench-top electrochemical advantage over Pt electrodes before and after the electrical stimulation program. In vivo, CH coated electrodes also had a significant advantage over Pt electrodes throughout the stimulation program, exhibiting higher CSC (p= 0.002), larger CIL (p = 0.002), and lower VT impedance (p < 0.001). The CH cohort exhibited a greater tissue response (p= 0.003) with small deposits of particulate material within the tissue capsule. There was no loss in auditory neuron density or change in neural response thresholds in any cochleae. Examination of the electrode surface revealed that most CH electrodes exhibited some coating loss; however, there was no evidence of corrosion in the underlying Pt. Significance. CH coated electrodes demonstrated significant electrochemical advantages on the bench-top and in vivo and maintained neural function despite an increased tissue response and coating loss. While further research is required to understand the cause of the coating loss, CH electrodes provide promise for use in neural prostheses.

Objective. To systematically compare the in vitro electrochemical and mechanical properties of several electrode coatings that have been reported to increase the efficacy of medical bionics devices by increasing the amount of charge that can be delivered safely to the target neural tissue. Approach. Smooth platinum (Pt) ring and disc electrodes were coated with reduced graphene oxide, conductive hydrogel, or electrodeposited Pt-Ir. Electrodes with coatings were compared with uncoated smooth Pt electrodes before and after an in vitro accelerated aging protocol. The various coatings were compared mechanically using the adhesion-by-tape test. Electrodes were stimulated in saline for 24 hours/day 7 days/week for 21 d at 85 °C (1.6-year equivalence) at a constant charge density of 200 µC/cm2/phase. Electrodes were graded on surface corrosion and trace analysis of Pt in the electrolyte after aging. Electrochemical measurements performed before, during, and after aging included electrochemical impedance spectroscopy, cyclic voltammetry, and charge injection limit and impedance from voltage transient recordings. Main results. All three coatings adhered well to smooth Pt and exhibited electrochemical advantage over smooth Pt electrodes prior to aging. After aging, graphene coated electrodes displayed a stimulation-induced increase in impedance and reduction in the charge injection limit (p < 0.001), alongside extensive corrosion and release of Pt into the electrolyte. In contrast, both conductive hydrogel and Pt-Ir coated electrodes had smaller impedances and larger charge injection limits than smooth Pt electrodes (p < 0.001) following aging regardless of the stimulus level and with little evidence of corrosion or Pt dissolution. Significance. This study rigorously tested the mechanical and electrochemical performance of electrode coatings in vitro and provided suitable candidates for future in vivo testing.

Chronic tinnitus is a debilitating condition which affects 10–20% of adults and can severely impact their quality of life. Currently there is no objective measure of tinnitus that can be used clinically. Clinical assessment of the condition uses subjective feedback from individuals which is not always reliable. We investigated the sensitivity of functional near-infrared spectroscopy (fNIRS) to differentiate individuals with and without tinnitus and to identify fNIRS features associated with subjective ratings of tinnitus severity. We recorded fNIRS signals in the resting state and in response to auditory or visual stimuli from 25 individuals with chronic tinnitus and 21 controls matched for age and hearing loss. Severity of tinnitus was rated using the Tinnitus Handicap Inventory and subjective ratings of tinnitus loudness and annoyance were measured on a visual analogue scale. Following statistical group comparisons, machine learning methods including feature extraction and classification were applied to the fNIRS features to classify patients with tinnitus and controls and differentiate tinnitus at different severity levels. Resting state measures of connectivity between temporal regions and frontal and occipital regions were significantly higher in patients with tinnitus compared to controls. In the tinnitus group, temporal-occipital connectivity showed a significant increase with subject ratings of loudness. Also in this group, both visual and auditory evoked responses were significantly reduced in the visual and auditory regions of interest respectively. Naïve Bayes classifiers were able to classify patients with tinnitus from controls with an accuracy of 78.3%. An accuracy of 87.32% was achieved using Neural Networks to differentiate patients with slight/ mild versus moderate/ severe tinnitus. Our findings show the feasibility of using fNIRS and machine learning to develop an objective measure of tinnitus. Such a measure would greatly benefi

Despite advancements in pharmacotherapies, glycemia is poorly controlled in type 2 diabetic patients. As the vagus nerve regulates energy metabolism, here we evaluated the effect various electrical vagus nerve stimulation strategies have on glycemia and glucose-regulating hormones, as a first step to developing a novel therapy of type 2 diabetes. Sprague-Dawley rats were anesthetized, the abdominal (anterior) vagus nerve implanted, and various stimulation strategies applied to the nerve: (a) 15 Hz; (b) 4 kHz, or 40 kHz and; (c) a combination of 15 Hz and 40 kHz to directionally activate afferent or efferent vagal fibers. Following a glucose bolus (500 mg/kg, I.V.), stimulation strategies were applied (60 min) and serial blood samples taken. No stimulation was used as a crossover control sequence. Applying 15 Hz stimulation significantly increased glucose (+2.9 ± 0.2 mM·hr, p = .015) and glucagon (+17.1 ± 8.0 pg·hr/ml, p = .022), compared to no stimulation. Application of 4 kHz stimulation also significantly increased glucose levels (+1.5 ± 0.5 mM·hr, p = .049), while 40 kHz frequency stimulation resulted in no changes to glucose levels but did significantly lower glucagon (-12.3 ± 1.1 pg·hr/ml, p = .0009). Directional afferent stimulation increased glucose (+2.4 ± 1.5 mM·hr) and glucagon levels (+39.5 ± 15.0 pg·hr/ml). Despite hyperglycemia resulting when VNS, aVNS, and 4 kHz stimulation strategies were applied, the changes in insulin levels were not significant (p ≥ .05). In summary, vagus nerve stimulation modulates glycemia by effecting glucagon and insulin secretions, and high-frequency 40 kHz stimulation may have potential application for the treatment of type 2 diabetes.

Chronic tinnitus is a debilitating condition which affects 10-20% of adults and can severely impact their quality of life. Currently there is no objective measure of tinnitus that can be used clinically. Clinical assessment of the condition uses subjective feedback from individuals which is not always reliable. We investigated the sensitivity of functional near-infrared spectroscopy (fNIRS) to differentiate individuals with and without tinnitus and to identify fNIRS features associated with subjective ratings of tinnitus severity. We recorded fNIRS signals in the resting state and in response to auditory or visual stimuli from 25 individuals with chronic tinnitus and 21 controls matched for age and hearing loss. Severity of tinnitus was rated using the Tinnitus Handicap Inventory and subjective ratings of tinnitus loudness and annoyance were measured on a visual analogue scale. Following statistical group comparisons, machine learning methods including feature extraction and classification were applied to the fNIRS features to classify patients with tinnitus and controls and differentiate tinnitus at different severity levels. Resting state measures of connectivity between temporal regions and frontal and occipital regions were significantly higher in patients with tinnitus compared to controls. In the tinnitus group, temporal-occipital connectivity showed a significant increase with subject ratings of loudness. Also in this group, both visual and auditory evoked responses were significantly reduced in the visual and auditory regions of interest respectively. Naïve Bayes classifiers were able to classify patients with tinnitus from controls with an accuracy of 78.3%. An accuracy of 87.32% was achieved using Neural Networks to differentiate patients with slight/ mild versus moderate/ severe tinnitus. Our findings show the feasibility of using fNIRS and machine learning to develop an objective measure of tinnitus. Such a measure would greatly benefit clinicians and pa

Electrical stimulation has been used for decades in devices such as pacemakers, cochlear implants and more recently for deep brain and retinal stimulation and electroceutical treatment of disease. However, current spread from the electrodes limits the precision of neural activation, leading to a low quality therapeutic outcome or undesired side-effects. Alternative methods of neural stimulation such as optical stimulation offer the potential to deliver higher spatial resolution of neural activation. Direct optical stimulation is possible with infrared light, while visible light can be used to activate neurons if the neural tissue is genetically modified with a light sensitive ion channel. Experimentally, both methods have resulted in highly precise stimulation with little spread of activation at least in the cochlea, each with advantages and disadvantages. Infrared neural stimulation does not require modification of the neural tissue, but has very high power requirements. Optogenetics can achieve precision of activation with lower power, but only in conjunction with targeted insertion of a light sensitive ion channel into the nervous system via gene therapy. This review will examine the advantages and limitations of optical stimulation of neural tissue, using the cochlea as an exemplary model and recent developments for retinal and deep brain stimulation.

Bioelectronic medical devices are well established and widely used in the treatment of urological dysfunction. Approved targets include the sacral S3 spinal root and posterior tibial nerve, but an alternate target is the group of pelvic splanchnic nerves, as these contain sacral visceral sensory and autonomic motor pathways that coordinate storage and voiding functions of the bladder. Here, we developed a device suitable for long-term use in an awake rat model to study electrical neuromodulation of the pelvic nerve (homolog of the human pelvic splanchnic nerves). In male Sprague-Dawley rats, custom planar four-electrode arrays were implanted over the distal end of the pelvic nerve, close to the major pelvic ganglion. Electrically evoked compound action potentials (ECAPs) were reliably detected under anesthesia and in chronically implanted, awake rats up to 8 weeks post-surgery. ECAP waveforms showed three peaks, with latencies that suggested electrical stimulation activated several subpopulations of myelinated A-fiber and unmyelinated C-fiber axons. Chronic implantation of the array did not impact on voiding evoked in awake rats by continuous cystometry, where void parameters were comparable to those published in naïve rats. Electrical stimulation with chronically implanted arrays also induced two classes of bladder pressure responses detected by continuous flow cystometry in awake rats: voiding contractions and non-voiding contractions. No evidence of tissue pathology produced by chronically implanted arrays was detected by immunohistochemical visualization of markers for neuronal injury or noxious spinal cord activation. These results demonstrate a rat pelvic nerve electrode array that can be used for preclinical development of closed loop neuromodulation devices targeting the pelvic nerve as a therapy for neuro-urological dysfunction.

OBJECTIVE: Compared to electrical stimulation, optogenetic stimulation has the potential to improve the spatial precision of neural activation in neuroprostheses, but it requires intense light and has relatively poor temporal kinetics. We tested the effect of hybrid stimulation, which is the combination of subthreshold optical and electrical stimuli, on spectral and temporal fidelity in the cochlea by recording multiunit activity in the inferior colliculus of channelrhodopsin (H134R variant) transgenic mice. APPROACH: Pulsed light or biphasic electrical pulses were delivered to cochlear spiral ganglion neurons of acutely deafened mice, either as individual stimuli or as hybrid stimuli for which the timing of the electrical pulse had a varied delay relative to the start of the optical pulse. Response thresholds, spread of activation and entrainment data were obtained from multi-unit recordings from the auditory midbrain. MAIN RESULTS: Facilitation occurred when subthreshold electrical stimuli were applied at the end of, or up to 3.75 ms after subthreshold optical pulses. The spread of activation resulting from hybrid stimulation was significantly narrower than electrical-only and optical-only stimulation (p < 0.01), measured at equivalent suprathreshold levels of loudness that are relevant to cochlear implant users. Furthermore, temporal fidelity, measured as maximum following rates to 300 ms pulse trains bursts up to 240 Hz, was 2.4-fold greater than optical-only stimulation (p < 0.05). SIGNIFICANCE: By significantly improving spectral resolution of electrical- and optical-only stimulation and the temporal fidelity of optical-only stimulation, hybrid stimulation has the potential to increase the number of perceptually independent stimulating channels in a cochlear implant.

Electrical stimulation of the cervical vagus nerve is an emerging treatment for inflammatory bowel disease (IBD). However, side effects from cervical vagal nerve stimulation (VNS) are often reported by patients. Here we hypothesized that stimulating the vagus nerve closer to the end organ will have fewer off-target effects and will effectively reduce intestinal inflammation. Specifically, we aimed to: (i) compare off-target effects during abdominal and cervical VNS; (ii) verify that VNS levels were suprathreshold; and (iii) determine whether abdominal VNS reduces chemically-induced intestinal inflammation in rats. An electrode array was developed in-house to stimulate and record vagal neural responses. In a non-recovery experiment, stimulation-induced off-target effects were measured by implanting the cervical and abdominal vagus nerves of anaesthetized rats (n = 5) and recording changes to heart rate, respiration and blood pressure during stimulation (10 Hz; symmetric biphasic current pulse; 320 nC per phase). In a chronic experiment, the efficacy of VNS treatment was assessed by implanting an electrode array onto the abdominal vagus nerve and recording in vivo electrically-evoked neural responses during the implantation period. After 14 days, the intestine was inflamed with TNBS (2.5% 2,4,6-trinitrobenzene sulphonic acid) and rats received therapeutic VNS (n = 7; 10 Hz; 320 nC per phase; 3 h/day) or no stimulation (n = 8) for 4.5 days. Stool quality, plasma C-reactive protein and histology of the inflamed intestine were assessed. Data show that abdominal VNS had no effect (two-way RM-ANOVA: P ≥ 0.05) on cardiac, respiratory and blood pressure parameters. However, during cervical VNS heart rate decreased by 31 ± 9 beats/minute (P ≥ 0.05), respiration was inhibited and blood pressure decreased. Data addressing efficacy of VNS treatment show that electrically-evoked neural response thresholds remained stable (one-way RM ANOVA: P ≥ 0.05) and therapeutic stimulation re

Purpose: Shifting the region-of-interest within the input image to compensate for gaze shifts (‘‘gaze compensation’’) may improve hand–eye coordination in visual prostheses that incorporate an external camera. The present study investigated the effects of eye movement on hand-eye coordination under simulated prosthetic vision (SPV), and measured the coordination benefits of gaze compensation. Methods: Seven healthy-sighted subjects performed a target localization-pointing task under SPV. Three conditions were tested, modeling: retinally stabilized phosphenes (uncompensated); gaze compensation; and no phosphene movement (center-fixed). The error in pointing was quantified for each condition. Results: Gaze compensation yielded a significantly smaller pointing error than the uncompensated condition for six of seven subjects, and a similar or smaller pointing error than the center-fixed condition for all subjects (two-way ANOVA, P < 0.05). Pointing error eccentricity and gaze eccentricity were moderately correlated in the uncompensated condition (azimuth: R2 = 0.47; elevation: R2 = 0.51) but not in the gaze-compensated condition (azimuth: R2 = 0.01; elevation: R2 = 0.00). Increased variability in gaze at the time of pointing was correlated with greater reduction in pointing error in the center-fixed condition compared with the uncompensated condition (R2 = 0.64). Conclusions: Eccentric eye position impedes hand–eye coordination in SPV. While limiting eye eccentricity in uncompensated viewing can reduce errors, gaze compensation is effective in improving coordination for subjects unable to maintain fixation. Translational Relevance: The results highlight the present necessity for suppressing eye movement and support the use of gaze compensation to improve hand–eye coordination and localization performance in prosthetic vision.

Inflammatory damage to the bowel, as occurs in inflammatory bowel disease (IBD), is debilitating to patients. In both patients and animal experimental models, histological analyses of biopsies and endoscopic examinations are used to evaluate the disease state. However, such measurements often have delays and are invasive, while endoscopy is not quantitatively objective. Therefore, a real-time quantitative method to assess compromised mucosal barrier function is advantageous. We investigated the correlation of in vivo changes in electrical transmural impedance with histological measures of inflammation. Four platinum (Pt) ball electrodes were placed in the lumen of the rat small intestine, with a return electrode under the skin. Electrodes placed within the non-inflamed intestine generated stable impedances during the 3 h testing period. Following an intraluminal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), an established animal model of IBD, impedances in the inflamed region significantly decreased relative to a region not exposed to TNBS (p < 0.05). Changes in intestinal transmural impedance were correlated (p < 0.05) with histologically assessed damage to the mucosa and increases in neutrophil, eosinophil and T-cell populations at 3 h compared with tissue from control regions. This quantitative, real-time assay may have application in the diagnosis and clinical management of IBD.

Deep brain stimulation (DBS) is a rapidly expanding treatment for neurological and psychiatric conditions; however, a target-specific biomarker is required to optimize therapy. Here, we show that DBS evokes a large-amplitude resonant neural response focally in the subthalamic nucleus. This response is greatest in the dorsal region (the clinically optimal stimulation target for Parkinson disease), coincides with improved clinical performance, is chronically recordable, and is present under general anesthesia. These features make it a readily utilizable electrophysiological signal that could potentially be used for guiding electrode implantation surgery and tailoring DBS therapy to improve patient outcomes. Ann Neurol 2018;83:1027-1031.

Accurate perception of time-variant pitch is important for speech recognition, particularly for tonal languages with different lexical tones such as Mandarin, in which different tones convey different semantic information. Previous studies reported that the auditory nerve and cochlear nucleus can encode different pitches through phase-locked neural activities. However, little is known about how the inferior colliculus (IC) encodes the time-variant periodicity pitch of natural speech. In this study, the Mandarin syllable /ba/ pronounced with four lexical tones (flat, rising, falling then rising and falling) were used as stimuli. Local field potentials (LFPs) and single neuron activity were simultaneously recorded from 90 sites within contralateral IC of six urethane-anesthetized and decerebrate guinea pigs in response to the four stimuli. Analysis of the temporal information of LFPs showed that 93% of the LFPs exhibited robust encoding of periodicity pitch. Pitch strength of LFPs derived from the autocorrelogram was significantly (p < 0.001) stronger for rising tones than flat and falling tones. Pitch strength are also significantly increased (p < 0.05) with the characteristic frequency (CF). On the other hand, only 47% (42 or 90) of single neuron activities were significantly synchronized to the fundamental frequency of the stimulus suggesting that the temporal spiking pattern of single IC neuron could encode the time variant periodicity pitch of speech robustly. The difference between the number of LFPs and single neurons that encode the time-variant F0 voice pitch supports the notion of a transition at the level of IC from direct temporal coding in the spike trains of individual neurons to other form of neural representation.

OBJECTIVE: Focused multipolar (FMP) stimulation has been shown to produce restricted neural activation using intracochlear stimulation in animals with a normal population of spiral ganglion neurons (SGNs). However, in a clinical setting, the widespread loss of SGNs and peripheral fibres following deafness is expected to influence the effectiveness of FMP. APPROACH: We compared the efficacy of FMP stimulation to both monopolar (MP) and tripolar (TP) stimulation in long-term deafened cat cochleae (n = 8). Unlike our previous study, these cochleae contained <10% of the normal SGN population adjacent to the electrode array. We also evaluated the effect of electrode position on stimulation modes by using either modiolar facing or lateral wall facing half-band electrodes. The spread of neural activity across the inferior colliculus, a major nucleus within the central auditory pathway, was used as a measure of spatial selectivity. MAIN RESULTS: In cochleae with significant SGN degeneration, we observed that FMP and TP stimulation resulted in greater spatial selectivity than MP stimulation (p < 0.001). However, thresholds were significantly higher for FMP and TP stimulation compared to MP stimulation (p < 0.001). No difference between FMP and TP stimulation was found in any measures. The high threshold levels for FMP stimulation was significantly reduced without compromising spatial selectivity by varying the degree of current focusing (referred as 'partial-FMP' stimulation). Spatial selectivity of all stimulation modes was unaffected by the electrode position. Finally, spatial selectivity in long-term deafened cochleae was significantly less than that of cochleae with normal SGN population (George S S et al 2014 J. Neural Eng. 11 065003). SIGNIFICANCE: The present results indicate that the greater spatial selectivity of FMP and TP stimulation over MP stimulation is maintained in cochleae with significant neural degeneration and is not adversely affected by electrode positi

Animal behavioral studies make a significant contribution to hearing research and provide vital information which is not available from human subjects. Animal psychoacoustics is usually extremely time consuming and labor intensive; in addition, animals may become stressed, especially if restraints or negative reinforcers such as electric shocks are used. We present a novel behavioral experimental system that was developed to allow efficient animal training in response to acoustic stimuli. Cats were required to perform a relatively simple task of moving toward and away from the device depending on whether the members of a tone pair were different or the same in frequency (go/no-go task). The experimental setup proved to be effective, with all animals (N = 7) performing at above 90% correct on an easy task. Animals were trained within 2-4 weeks and then generated a total of 150-200 trials per day, distributed within approximately 8 self initiated sessions. Data collected using this system were stable over 1 week and repeatable over long test periods (14 weeks). Measured frequency discrimination thresholds from 3 animals at 3 different reference frequencies were comparable with previously published results. The main advantages of the system are: relatively simple setup; large amounts of data can be generated without the need of researcher supervision; multiple animals can be tested simultaneously without removal from home pens; and no electric shocks or restraints are required.

OBJECTIVE: The conductive nature of the fluids and tissues of the cochlea can lead to broad activation of spiral ganglion neurons using contemporary cochlear implant stimulation configurations such as monopolar (MP) stimulation. The relatively poor spatial selectivity is thought to limit implant performance, particularly in noisy environments. Several current focusing techniques have been proposed to reduce the spread of activation with the aim towards achieving improved clinical performance. APPROACH: The present research evaluated the efficacy of focused multipolar (FMP) stimulation, a relatively new focusing technique in the cochlea, and compared its efficacy to both MP stimulation and tripolar (TP) stimulation. The spread of neural activity across the inferior colliculus (IC), measured by recording the spatial tuning curve, was used as a measure of spatial selectivity. Adult cats (n = 6) were acutely deafened and implanted with an intracochlear electrode array before multi-unit responses were recorded across the cochleotopic gradient of the contralateral IC. Recordings were made in response to acoustic and electrical stimulation using the MP, TP and FMP configurations. MAIN RESULTS: FMP and TP stimulation resulted in greater spatial selectivity than MP stimulation. However, thresholds were significantly higher (p < 0.001) for FMP and TP stimulation compared to MP stimulation. There were no differences found in spatial selectivity and threshold between FMP and TP stimulation. SIGNIFICANCE: The greater spatial selectivity of FMP and TP stimulation would be expected to result in improved clinical performance. However, further research will be required to demonstrate the efficacy of these modes of stimulation after longer durations of deafness.

We have previously shown that neonatal deafness of 7-13 months duration leads to loss of cochleotopy in the primary auditory cortex (AI) that can be reversed by cochlear implant use. Here we describe the effects of a similar duration of deafness and cochlear implant use on temporal processing. Specifically, we compared the temporal resolution of neurons in AI of young adult normal-hearing cats that were acutely deafened and implanted immediately prior to recording with that in three groups of neonatally deafened cats. One group of neonatally deafened cats received no chronic stimulation. The other two groups received up to 8 months of either low- or high-rate (50 or 500 pulses per second per electrode, respectively) stimulation from a clinical cochlear implant, initiated at 10 weeks of age. Deafness of 7-13 months duration had no effect on the duration of post-onset response suppression, latency, latency jitter, or the stimulus repetition rate at which units responded maximally (best repetition rate), but resulted in a statistically significant reduction in the ability of units to respond to every stimulus in a train (maximum following rate). None of the temporal response characteristics of the low-rate group differed from those in acutely deafened controls. In contrast, high-rate stimulation had diverse effects: it resulted in decreased suppression duration, longer latency and greater jitter relative to all other groups, and an increase in best repetition rate and cut-off rate relative to acutely deafened controls. The minimal effects of moderate-duration deafness on temporal processing in the present study are in contrast to its previously-reported pronounced effects on cochleotopy. Much longer periods of deafness have been reported to result in significant changes in temporal processing, in accord with the fact that duration of deafness is a major factor influencing outcome in human cochlear implantees.

An optical fiber-based sensor has been developed to measure the forces at the tip of an electrode array during insertion into the cochlea. The sensor, utilizing optical fiber Bragg grating technology, was incorporated into a custom-designed Pt-banded electrode array for guinea pigs. In vivo experiments were undertaken in which forces at the tip of the array were measured in real time during the insertion. Data were obtained for maximum insertion forces of up to 254 mN. Histology was performed on the excised cochleae with the sensors fixed in position to evaluate the level of insertion trauma. The insertion experiments demonstrated a clear correlation between the applied force and collateral tissue damage.

Extended periods of deafness have profound effects on central auditory system function and organization. Neonatal deafening results in loss of the normal cochleotopic organization of the primary auditory cortex (AI), but environmentally-derived intracochlear electrical stimulation, via a cochlear implant, initiated shortly after deafening, can prevent this loss. We investigated whether such stimulation initiated after an extended period of deafness can restore cochleotopy. In two groups of neonatally-deafened cats, a multi-channel intracochlear electrode array was implanted at 8 weeks of age. One group received only minimal stimulation, associated with brief recordings at 4-6-week intervals, over the following 6 months to check the efficacy of the implant. In the other group, this 6-month period was followed by 6 months of near-continuous intracochlear electrical stimulation from a modified clinical cochlear implant system. We recorded multi-unit clusters in the auditory cortex and used two different methods to define the region of interest in the putative AI. There was no evidence of cochleotopy in any of the minimally stimulated animals, confirming our earlier finding. In three of six chronically stimulated cats there was clear evidence of AI cochleotopy, and in a fourth cat in which the majority of penetrations were in the anterior auditory field there was clear evidence of cochleotopy in that field. The finding that chronic intracochlear electrical stimulation after an extended period of deafness is able to restore cochleotopy in some (but not all) cases has implications for the performance of patients implanted after an extended period of deafness.

OBJECTIVE: Cochlear implants (CIs) have provided some auditory function to hundreds of thousands of people around the world. Although traditionally carried out only in profoundly deaf patients, the eligibility criteria for implantation have recently been relaxed to include many partially-deaf patients with useful levels of hearing. These patients receive both electrical stimulation from their implant and acoustic stimulation via their residual hearing (electro-acoustic stimulation; EAS) and perform very well. It is unclear how EAS improves speech perception over electrical stimulation alone, and little evidence exists about the nature of the interactions between electric and acoustic stimuli. Furthermore, clinical results suggest that some patients that undergo cochlear implantation lose some, if not all, of their residual hearing, reducing the advantages of EAS over electrical stimulation alone. A reliable animal model with clinically-relevant partial deafness combined with clinical CIs is important to enable these issues to be studied. This paper outlines such a model that has been successfully used in our laboratory. APPROACH: This paper outlines a battery of techniques used in our laboratory to generate, validate and examine an animal model of partial deafness and chronic CI use. MAIN RESULTS: Ototoxic deafening produced bilaterally symmetrical hearing thresholds in neonatal and adult animals. Electrical activation of the auditory system was confirmed, and all animals were chronically stimulated via adapted clinical CIs. Acoustic compound action potentials (CAPs) were obtained from partially-hearing cochleae, using the CI amplifier. Immunohistochemical analysis allows the effects of deafness and electrical stimulation on cell survival to be studied. SIGNIFICANCE: This animal model has applications in EAS research, including investigating the functional interactions between electric and acoustic stimulation, and the development of techniques to maintain residual

The aim of this study was to determine the effects of cochlear implant (CI) use on behavioral frequency discrimination ability in partially deafened cats. We hypothesized that the additional information provided by the CI would allow subjects to perform better on a frequency discrimination task. Four cats with a high frequency hearing loss induced by ototoxic drugs were first trained on a go/no-go, positive reinforcement, frequency discrimination task and reached asymptotic performance (measured by d' - detection theory). Reference frequencies (1, 4, and 7 kHz) were systematically rotated (Block design) every 9-11 days to cover the hearing range of the cats while avoiding bias arising from the order of testing. Animals were then implanted with an intracochlear electrode array connected to a CI and speech processor. They then underwent 6 months of continuous performance measurement with the CI turned on, except for one month when the stimulator was turned off. Overall, subjects performed the frequency discrimination task significantly better with their CI turned on than in the CI-off condition (3-way ANOVA, p < 0.001). The analysis showed no dependence on subject (3-way ANOVA, subject × on-off condition, p > 0.5); however, the CI only significantly improved performance for two (1 and 7 kHz) of the three reference frequencies. In this study we were able to show, for the first time, that cats can utilize information provided by a CI in performing a behavioral frequency discrimination task.

PURPOSE: Retinal prostheses are an approved treatment for vision restoration in retinal degenerative diseases; however, present implants have limited resolution and simply increasing the number of electrodes is limited by design issues. In cochlear implants, virtual electrodes can be created by simultaneous stimulation of adjacent physical electrodes (current steering). The present study assessed whether this type of current steering can be adapted for retinal implants. METHODS: Suprachoroidal electrode arrays were implanted in four normally sighted cat eyes. Electrode pairs were driven simultaneously at different current levels and current ratios. Multiunit spiking activity in the visual cortex was recorded. Spike distribution across channels enabled generation of cortical activation maps and calculation of centroid positions. For each current configuration, centroid shifts between two virtual electrodes were compared to shifts obtained from physical electrode stimulation. RESULTS: Using current steering, virtual electrodes with different cortical activation maps could be created. Cortical centroids were found to shift as a function of the current ratio used for virtual electrodes and were similar to the centroid shifts seen when using physical electrodes. In addition, the cortical response to stimulation of a physical electrode could be reproduced by applying current steering to electrodes on either side of the physical electrode. CONCLUSIONS: These results suggest that current steering can alter activation patterns in the visual cortex and could enhance visual perception in retinal implants by eliciting phosphene percepts intermediate between those elicited by physical electrodes. These results inform development of new electrode arrays that can take advantage of current steering.

Cochlear implants have provided hearing to hundreds of thousands of profoundly deaf people around the world. Recently, the eligibility criteria for cochlear implantation have been relaxed to include individuals who have some useful residual hearing. These recipients receive inputs from both electric and acoustic stimulation (EAS). Implant recipients who can combine these hearing modalities demonstrate pronounced benefit in speech perception, listening in background noise, and music appreciation over implant recipients that rely on electrical stimulation alone. The mechanisms bestowing this benefit are unknown, but it is likely that interaction of the electric and acoustic signals in the auditory pathway plays a role. Protection of residual hearing both during and following cochlear implantation is critical for EAS. A number of surgical refinements have been implemented to protect residual hearing, and the development of hearing-protective drug and gene therapies is promising for EAS recipients. This review outlines the current field of EAS, with a focus on interactions that are observed between these modalities in animal models. It also outlines current trends in EAS surgery and gives an overview of the drug and gene therapies that are clinically translatable and may one day provide protection of residual hearing for cochlear implant recipients.

OBJECTIVE: Neural responses to biphasic constant current pulses depend on stimulus pulse parameters such as polarity, duration, amplitude and interphase gap. The objective of this study was to systematically evaluate and optimize stimulus pulse parameters for a suprachoroidal retinal prosthesis. APPROACH: Normally sighted cats were acutely implanted with platinum electrode arrays in the suprachoroidal space. Monopolar stimulation comprised of monophasic and biphasic constant current pulses with varying polarity, pulse duration and interphase gap. Multiunit responses to electrical stimulation were recorded in the visual cortex. MAIN RESULTS: Anodal stimulation elicited cortical responses with shorter latencies and required lower charge per phase than cathodal stimulation. Clinically relevant retinal stimulation required relatively larger charge per phase compared with other neural prostheses. Increasing the interphase gap of biphasic pulses reduced the threshold of activation; however, the benefits of using an interphase gap need to be considered in light of the pulse duration and polarity used and other stimulation constraints. Based on our results, anodal first biphasic pulses between 300-1200 µs are recommended for suprachoroidal retinal stimulation. SIGNIFICANCE: These results provide insights into the efficacy of different pulse parameters for suprachoroidal retinal stimulation and have implications for the design of safe and clinically relevant stimulators for retinal prostheses.

The mouse is becoming an increasingly attractive model for auditory research due to the number of genetic deafness models available. These genetic models offer the researcher an array of congenital causes of hearing impairment, and are therefore of high clinical relevance. To date, the use of mice in cochlear implant research has not been possible due to the lack of an intracochlear electrode array and stimulator small enough for murine use, coupled with the difficulty of the surgery in this species. Here, we present a fully-implantable intracochlear electrode stimulator assembly designed for chronic implantation in the mouse. We describe the surgical approach for implantation, as well as presenting the first functional data obtained from intracochlear electrical stimulation in the mouse.

Cochlear implant users have limited ability to understand speech in noisy conditions. Signal processing methods to address this issue that use multiple microphones typically use beamforming to perform noise reduction. However, the effectiveness of the beamformer is diminished as the number of interfering noises increases and the acoustic environment becomes more diffuse. A multi-microphone noise reduction algorithm that aims to address this issue is presented in this study. The algorithm uses spatial filtering to estimate the signal-to-noise ratio (SNR) and attenuates time-frequency elements that have poor SNR. The algorithm was evaluated by measuring intelligibility of speech embedded in 4-talker babble where the interfering talkers were spatially separated and changed location during the test. Twelve cochlear implant users took part in the evaluation, which demonstrated a significant mean improvement of 4.6 dB (standard error 0.4, P < 0.001) in speech reception threshold compared to an adaptive beamformer. The results suggest that a substantial improvement in performance can be gained for cochlear implant users in noisy environments where the noise is spatially separated from the target speech.

Cochlear implants restore hearing cues in the severe-profoundly deaf by electrically stimulating spiral ganglion neurons (SGNs). However, SGNs degenerate following loss of cochlear hair cells, due at least in part to a reduction in the endogenous neurotrophin (NT) supply, normally provided by hair cells and supporting cells of the organ of Corti. Delivering exogenous NTs to the cochlea can rescue SGNs from degeneration and can also promote the ectopic growth of SGN neurites. This resprouting may disrupt the cochleotopic organization upon which cochlear implants rely to impart pitch cues. Using retrograde labeling and confocal imaging of SGNs, we determined the extent of neurite growth following 28 days of exogenous NT treatment in deafened guinea pigs with and without chronic electrical stimulation (ES). On completion of this treatment, we measured the spread of neural activation to intracochlear ES by recording neural responses across the cochleotopically organized inferior colliculus using multichannel recording techniques. Although NT treatment significantly increased both the length and the lateral extent of growth of neurites along the cochlea compared with deafened controls, these anatomical changes did not affect the spread of neural activation when examined immediately after 28 days of NT treatment. NT treatment did, however, result in lower excitation thresholds compared with deafened controls. These data support the application of NTs for improved clinical outcomes for cochlear implant patients.

Sensorineural hearing loss is associated with gradual degeneration of spiral ganglion neurons (SGNs), compromising hearing outcomes with cochlear implant use. Combination of neurotrophin delivery to the cochlea and electrical stimulation from a cochlear implant protects SGNs, prompting research into neurotrophin-eluting polymer electrode coatings. The electrically conducting polypyrrole/para-toluene sulfonate containing neurotrophin-3 (Ppy/pTS/NT3) was applied to 1.7 mm2 cochlear implant electrodes. Ppy/pTS/NT3-coated electrode arrays stored 2 ng NT3 and released 0.1 ng/day with electrical stimulation. Guinea pigs were implanted with Ppy/pTS or Ppy/pTS/NT3 electrode arrays two weeks after deafening via aminoglycosides. The electrodes of a subgroup of these guinea pigs were electrically stimulated for 8 h/day for 2 weeks. There was a loss of SGNs in the implanted cochleae of guinea pigs with Ppy/pTS-coated electrodes indicative of electrode insertion damage. However, guinea pigs implanted with electrically stimulated Ppy/pTS/NT3-coated electrodes had lower electrically-evoked auditory brainstem response thresholds and greater SGN densities in implanted cochleae compared to non-implanted cochleae and compared to animals implanted with Ppy/pTS-coated electrodes (p<0.05). Ppy/pTS/NT3 did not exacerbate fibrous tissue formation and did not affect electrode impedance. Drug-eluting conducting polymer coatings on cochlear implant electrodes present a clinically viable method to promote preservation of SGNs without adversely affecting the function of the cochlear implant.

An in vitro preparation of the guinea-pig cornea was used to study the effects of changing temperature on nerve terminal impulses recorded extracellularly from cold-sensitive receptors. At a stable holding temperature (31-32.5 degrees C), cold receptors had an ongoing periodic discharge of nerve terminal impulses. This activity decreased or ceased with heating and increased with cooling. Reducing the rate of temperature change reduced the respective effects of heating and cooling on nerve terminal impulse frequency. In addition to changes in the frequency of activity, nerve terminal impulse shape also changed with heating and cooling. At the same ambient temperature, nerve terminal impulses were larger in amplitude and faster in time course during heating than those recorded during cooling. The magnitude of these effects of heating and cooling on nerve terminal impulse shape was reduced if the rate of temperature change was slowed. At 29, 31.5, and 35 degrees C, a train of 50 electrical stimuli delivered to the ciliary nerves at 10-40 Hz produced a progressive increase in the amplitude of successive nerve terminal impulses evoked during the train. Therefore, it is unlikely that the reduction in nerve terminal impulse amplitude observed during cooling is due to the activity-dependent changes in the nerve terminal produced by the concomitant increase in impulse frequency. Instead, the differences in nerve terminal impulse shape observed at the same ambient temperature during heating and cooling may reflect changes in the membrane potential of the nerve terminal associated with thermal transduction.