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1.  Chronic Electrical Stimulation with a Suprachoroidal Retinal Prosthesis: A Preclinical Safety and Efficacy Study 
PLoS ONE  2014;9(5):e97182.
Purpose
To assess the safety and efficacy of chronic electrical stimulation of the retina with a suprachoroidal visual prosthesis.
Methods
Seven normally-sighted feline subjects were implanted for 96–143 days with a suprachoroidal electrode array and six were chronically stimulated for 70–105 days at levels that activated the visual cortex. Charge balanced, biphasic, current pulses were delivered to platinum electrodes in a monopolar stimulation mode. Retinal integrity/function and the mechanical stability of the implant were assessed monthly using electroretinography (ERG), optical coherence tomography (OCT) and fundus photography. Electrode impedances were measured weekly and electrically-evoked visual cortex potentials (eEVCPs) were measured monthly to verify that chronic stimuli were suprathreshold. At the end of the chronic stimulation period, thresholds were confirmed with multi-unit recordings from the visual cortex. Randomized, blinded histological assessments were performed by two pathologists to compare the stimulated and non-stimulated retina and adjacent tissue.
Results
All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. After an initial post-operative settling period, electrode arrays were mechanically stable. Mean electrode impedances were stable between 11–15 kΩ during the implantation period. Visually-evoked ERGs & OCT were normal, and mean eEVCP thresholds did not substantially differ over time. In 81 of 84 electrode-adjacent tissue samples examined, there were no discernible histopathological differences between stimulated and unstimulated tissue. In the remaining three tissue samples there were minor focal fibroblastic and acute inflammatory responses.
Conclusions
Chronic suprathreshold electrical stimulation of the retina using a suprachoroidal electrode array evoked a minimal tissue response and no adverse clinical or histological findings. Moreover, thresholds and electrode impedance remained stable for stimulation durations of up to 15 weeks. This study has demonstrated the safety and efficacy of suprachoroidal stimulation with charge balanced stimulus currents.
doi:10.1371/journal.pone.0097182
PMCID: PMC4031073  PMID: 24853376
2.  Spiral ganglion neuron survival and function in the deafened cochlea following chronic neurotrophic treatment 
Hearing research  2011;282(1-2):303-313.
Cochlear implants electrically stimulate residual spiral ganglion neurons (SGNs) to provide auditory cues for the severe-profoundly deaf. However, SGNs gradually degenerate following cochlear hair cell loss, leaving fewer neurons available for stimulation. Providing an exogenous supply of neurotrophins (NTs) has been shown to prevent SGN degeneration, and when combined with chronic intracochlear electrical stimulation (ES) following a short period of deafness (5 days), may also promote the formation of new neurons. The present study assessed the histopathological response of guinea pig cochleae treated with NTs (brain-derived neurotrophic factor and neurotrophin-3) with and without ES over a four week period, initiated two-weeks after deafening. Results were compared to both NT alone and artificial perilymph (AP) treated animals. AP/ES treated animals exhibited no evidence of SGN rescue compared with untreated deafened controls. In contrast, NT administration showed a significant SGN rescue effect in the lower and middle cochlear turns (two-way ANOVA, p < 0.05) compared with AP-treated control animals. ES in combination with NT did not enhance SGN survival compared with NT alone. SGN function was assessed by measuring electrically-evoked auditory brainstem response (EABR) thresholds. EABR thresholds following NT treatment were significantly lower than animals treated with AP (two-way ANOVA, p = 0.033). Finally, the potential for induced neurogenesis following the combined treatment was investigated using a marker of DNA synthesis. However, no evidence of neurogenesis was observed in the SGN population. The results indicate that chronic NT delivery to the cochlea may be beneficial to cochlear implant patients by increasing the number of viable SGNs and decreasing activation thresholds compared to chronic ES alone.
doi:10.1016/j.heares.2011.06.007
PMCID: PMC3205216  PMID: 21762764
deafness; neurotrophins; electrical stimulation; cochlear implant; spiral ganglion neurons; neurogenesis
3.  Combining Cell-Based Therapies and Neural Prostheses to Promote Neural Survival 
Neurotherapeutics  2011;8(4):774-787.
Cochlear implants provide partial restoration of hearing for profoundly deaf patients by electrically stimulating spiral ganglion neurons (SGNs); however, these neurons gradually degenerate following the onset of deafness. Although the exogenous application of neurotrophins (NTs) can prevent SGN loss, current techniques to administer NTs for long periods of time have limited clinical applicability. We have used encapsulated choroid plexus cells (NTCells; Living Cell Technologies, Auckland, New Zealand) to provide NTs in a clinically viable manner that can be combined with a cochlear implant. Neonatal cats were deafened and unilaterally implanted with NTCells and a cochlear implant. Animals received chronic electrical stimulation (ES) alone, NTs alone, or combined NTs and ES (ES + NT) for a period of as much as 8 months. The opposite ear served as a deafened unimplanted control. Chronic ES alone did not result in increased survival of SGNs or their peripheral processes. NT treatment alone resulted in greater SGN survival restricted to the upper basal cochlear region and an increased density of SGN peripheral processes. Importantly, chronic ES in combination with NTs provided significant SGN survival throughout a wider extent of the cochlea, in addition to an increased peripheral process density. Re-sprouting peripheral processes were observed in the scala media and scala tympani, raising the possibility of direct contact between peripheral processes and a cochlear implant electrode array. We conclude that cell-based therapy is clinically viable and effective in promoting SGN survival for extended durations of cochlear implant use. These findings have important implications for the safe delivery of therapeutic drugs to the cochlea.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-011-0070-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-011-0070-0
PMCID: PMC3250292  PMID: 21904788
Cell-based therapy; Cochlear implantation; Neurotrophin; Nerve protection; Electrical stimulation
4.  Cochlear Implants and Brain Plasticity 
Hearing research  2007;238(1-2):110-117.
Cochlear implants have been implanted in over 110,000 deaf adults and children worldwide and provide these patients with important auditory cues necessary for auditory awareness and speech perception via electrical stimulation of the auditory nerve (AN). In 1942 Woolsey & Walzl presented the first report of cortical responses to localised electrical stimulation of different sectors of the AN in normal hearing cats, and established the cochleotopic organization of the projections to primary auditory cortex. Subsequently, individual cortical neurons in normal hearing animals have been shown to have well characterized input-output functions for electrical stimulation and decreasing response latencies with increasing stimulus strength. However, the central auditory system is not immutable, and has a remarkable capacity for plastic change, even into adulthood, as a result of changes in afferent input. This capacity for change is likely to contribute to the ongoing clinical improvements observed in speech perception for cochlear implant users. This review examines the evidence for changes of the response properties of neurons in, and consequently the functional organization of, the central auditory system produced by chronic, behaviourally relevant, electrical stimulation of the AN in profoundly deaf humans and animals.
doi:10.1016/j.heares.2007.08.004
PMCID: PMC2361156  PMID: 17910997
Electrical Stimulation; Auditory Cortex; Plasticity; Cochleotopy; Reorganisation
5.  Cochlear Implants and Brain Plasticity 
British medical bulletin  2002;63:183-193.
Cochlear implants have been implanted in over 110,000 deaf adults and children worldwide and provide these patients with important auditory cues necessary for auditory awareness and speech perception via electrical stimulation of the auditory nerve (AN). In 1942 Woolsey & Walzl presented the first report of cortical responses to localised electrical stimulation of different sectors of the AN in normal hearing cats, and established the cochleotopic organization of the projections to primary auditory cortex. Subsequently, individual cortical neurons in normal hearing animals have been shown to have well characterized input-output functions for electrical stimulation and decreasing response latencies with increasing stimulus strength. However, the central auditory system is not immutable, and has a remarkable capacity for plastic change, even into adulthood, as a result of changes in afferent input. This capacity for change is likely to contribute to the ongoing clinical improvements observed in speech perception for cochlear implant users. This review examines the evidence for changes of the response properties of neurons in, and consequently the functional organization of, the central auditory system produced by chronic, behaviourally relevant, electrical stimulation of the AN in profoundly deaf humans and animals.
PMCID: PMC1988843  PMID: 12324393
Electrical Stimulation; Auditory Cortex; Plasticity; Cochleotopy; Reorganisation
6.  EFFECTS OF NEONATAL PARTIAL DEAFNESS AND CHRONIC INTRACOCHLEAR ELECTRICAL STIMULATION ON AUDITORY AND ELECTRICAL RESPONSE CHARACTERISTICS IN PRIMARY AUDITORY CORTEX 
Hearing research  2009;257(1-2):93-105.
The use of cochlear implants in patients with severe hearing losses but residual low-frequency hearing raises questions concerning the effects of chronic intracochlear electrical stimulation(ICES) on cortical responses to auditory and electrical stimuli. We investigated these questions by studying responses to tonal and electrical stimuli in primary auditory cortex (AI) of two groups of neonatally-deafened cats with residual high-threshold, low-frequency hearing. One group were implanted with a multi-channel intracochlear electrode at eight weeks of age, and received chronic ICES for up to nine months before cortical recording. Cats in the other group were implanted immediately prior to cortical recording as adults. In all cats in both groups, multi-neuron responses throughout the rostro-caudal extent of AI had low characteristic frequencies (CFs), in the frequency range of the residual hearing, and high-thresholds. Threshold and minimum latency at CF did not differ between the groups, but in the chronic ICES animals there was a higher proportion of electrically but not acoustically excited recording sites. Electrical response thresholds were higher and latencies shorter in the chronically stimulated animals. Thus, chronic implantation and ICES affected the extent of AI that could be activated by acoustic stimuli and resulted in changes in electrical response characteristics.
doi:10.1016/j.heares.2009.08.006
PMCID: PMC2803318  PMID: 19703532
Cochlear implant; auditory cortex; electrical stimulation; neural prosthesis; sensorineural hearing loss
7.  Neural Prostheses and Brain Plasticity 
Journal of neural engineering  2009;6(6):065008.
The success of modern neural prostheses is dependent on a complex interplay between the devices’ hardware and software and the dynamic environment in which the devices operate: the patient’s body or ‘wetware’. Over 110,000 severe/profoundly deaf individuals presently receive information enabling auditory awareness and speech perception from cochlear implants. The cochlear implant therefore provides a useful case study for a review of the complex interactions between hardware, software and wetware, and of the important role of the dynamic nature of wetware. This review will examine the evidence of changes in the wetware contributing to changes in speech perception and discuss how these changes relate to electrophysiological and functional imaging studies in humans. The relationship between the human data and evidence from animals of the remarkable capacity for plastic change of the central auditory system, even into adulthood, will then be examined. Finally, we will discuss the role of brain plasticity in neural prostheses in general.
doi:10.1088/1741-2560/6/6/065008
PMCID: PMC2935525  PMID: 19850976
8.  A Novel Stimulus Artifact Removal Technique for High-Rate Electrical Stimulation 
Journal of neuroscience methods  2008;170(2):277-284.
Electrical stimulus artifact corrupting electrophysiological recordings often make the subsequent analysis of the underlying neural response difficult. This is particularly evident when investigating short-latency neural activity in response to high-rate electrical stimulation. We developed and evaluated an off-line technique for the removal of stimulus artifact from electrophysiological recordings. Pulsatile electrical stimulation was presented at rates of up to 5000 pulses/s during extracellular recordings of guinea pig auditory nerve fibers. Stimulus artifact was removed by replacing the sample points at each stimulus artifact event with values interpolated along a straight line, computed from neighbouring sample points. This technique required only that artifact events be identifiable and that the artifact duration remained less than both the inter-stimulus interval and the time course of the action potential. We have demonstrated that this computationally efficient sample-and-interpolate technique removes the stimulus artifact with minimal distortion of the action potential waveform. We suggest that this technique may have potential applications in a range of electrophysiological recording systems.
doi:10.1016/j.jneumeth.2008.01.023
PMCID: PMC2396946  PMID: 18339428
Stimulus Artifact; Artifact Removal; Electrical Stimulation; Electrophysiology; Auditory Nerve
9.  Cochlear implant use following neonatal deafness influences the cochleotopic organization of the primary auditory cortex in cats 
Electrical stimulation of spiral ganglion neurons in deafened cochlea, via a cochlear implant, provides a means of investigating the effects of the removal and subsequent restoration of afferent input on the functional organization of the primary auditory cortex (AI). We neonatally deafened seventeen cats before the onset of hearing, thereby abolishing virtually all afferent input from the auditory periphery. In seven animals, the auditory pathway was chronically reactivated with environmentally-derived electrical stimuli presented via a multi-channel intracochlear electrode array implanted at eight weeks of age. Electrical stimulation was provided by a clinical cochlear implant that was used continuously for periods of up to seven months. In ten long-term deafened cats and three age-matched normal hearing controls, an intracochlear electrode array was implanted immediately prior to cortical recording. We recorded from a total of 812 single unit and multi-unit clusters in AI of all cats as adults, using a combination of single tungsten and multi-channel silicon electrode arrays. The absence of afferent activity in the long-term deafened animals had little effect on the basic response properties of AI neurons but resulted in complete loss of the normal cochleotopic organization of AI. This effect was almost completely reversed by chronic reactivation of the auditory pathway via the cochlear implant. We hypothesize that maintenance or re-establishment of a cochleotopically organized AI by activation of a restricted sector of the cochlea – as demonstrated in the present study - contributes to the remarkable clinical performance observed among human patients implanted at a young age.
doi:10.1002/cne.21886
PMCID: PMC2597008  PMID: 18972570
cortical plasticity; electrical stimulation; neural prosthesis; sensorineural hearing loss
10.  Does cochlear implantation and electrical stimulation affect residual hair cells and spiral ganglion neurons? 
Hearing research  2006;225(1-2):60-70.
Increasing numbers of cochlear implant subjects have some level of residual hearing at the time of implantation. The present study examined whether (i) hair cells that have survived one pathological insult (aminoglycoside deafening), can survive and function following long-term cochlear implantation and electrical stimulation (ES); and (ii) chronic ES in these cochleae results in greater trophic support of spiral ganglion neurons (SGNs) compared with cochleae devoid of hair cells. Eight cats, with either partial (n=4) or severe (n=4) sensorineural hearing loss, were bilaterally implanted with scala tympani electrode arrays 2 months after deafening, and received unilateral ES using charge balanced biphasic current pulses for periods of up to 235 days. Frequency-specific compound action potentials and click-evoked auditory brainstem responses (ABRs) were recorded periodically to monitor the residual acoustic hearing. Electrically-evoked ABRs (EABRs) were recorded to confirm the stimulus levels were 3-6 dB above the EABR threshold. On completion of the ES program the cochleae were examined histologically. Partially deafened animals showed no significant increase in acoustic thresholds over the implantation period. Moreover, chronic ES of an electrode array located in the base of the cochlea did not adversely affect hair cells in the middle or apical turns. There was evidence of a small but statistically significant rescue of SGNs in the middle and apical turns of stimulated cochleae in animals with partial hearing. Chronic ES did not, however, prevent a reduction in SGN density for the severely deaf cohort, although SGNs adjacent to the stimulating electrodes did exhibit a significant increase in soma area (p<0.01). In sum, chronic ES in partial hearing animals does not adversely affect functioning residual hair cells apical to the electrode array. Moreover, while there is an increase in the soma area of SGNs close to the stimulating electrodes in severely deaf cochleae, this trophic effect does not result in increased SGN survival.
doi:10.1016/j.heares.2006.12.004
PMCID: PMC1853285  PMID: 17258411
neural degeneration; auditory nerve; deafness; electrical stimulation; cochlear implant; electric-acoustic stimulation
11.  PLASTICITY IN THE ADULT CENTRAL AUDITORY SYSTEM 
The central auditory system retains into adulthood a remarkable capacity for plastic changes in the response characteristics of single neurons and the functional organization of groups of neurons. The most dramatic examples of this plasticity are provided by changes in frequency selectivity and organization as a consequence of either partial hearing loss or procedures that alter the significance of particular frequencies for the organism. Changes in temporal resolution are also seen as a consequence of altered experience. These forms of plasticity are likely to contribute to the improvements exhibited by cochlear implant users in the post-implantation period.
PMCID: PMC1892193  PMID: 17572797
12.  Effects of Heating and Cooling on Nerve Terminal Impulses Recorded from Cold-sensitive Receptors in the Guinea-pig Cornea 
The Journal of General Physiology  2003;121(5):427-439.
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°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°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.
doi:10.1085/jgp.200308814
PMCID: PMC2217380  PMID: 12695483
action potential; thermal transduction; sensory receptor; extracellular recording

Results 1-12 (12)