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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.  Nanoporous Peptide Particles for Encapsulating and Releasing Neurotrophic Factors in an Animal Model of Neurodegeneration 
Neurotrophin-BDNF can be effectively encapsulated in nanoporous poly(L-glutamic acid) particles prepared via mesoporous silica templating. The loaded BDNF can be released in a sustained manner with maintained biological activity. Animal experiments demonstrate the released BDNF can efficiently rescue the auditory neurons (as indicated by the arrows) in the cochlea of guinea pigs with sensorineural hearing loss.
doi:10.1002/adma.201200634
PMCID: PMC3543853  PMID: 22610659
Mesoporous silica; Nanoporous polymer particle; Drug delivery; Neurotrophic factors; Sensorineural hearing loss
4.  Hydrogel limits stem cell dispersal in the deaf cochlea: implications for cochlear implants 
Journal of neural engineering  2012;9(6):065001.
Auditory neurons provide the critical link between a cochlear implant and the brain in deaf individuals, therefore their preservation and/or regeneration is important for optimal performance of this neural prosthesis. In cases where auditory neurons are significantly depleted, stem cells (SCs) may be used to replace the lost population of neurons, thereby re-establishing the critical link between the periphery (implant) and the brain. For such a therapy to be therapeutically viable, SCs must be differentiated into neurons, retained at their delivery site and damage caused to the residual auditory neurons minimized. Here we describe the transplantation of SC-derived neurons into the deaf cochlea, using a peptide hydrogel to limit their dispersal. The described approach illustrates that SCs can be delivered to and are retained within the basal turn of the cochlea, without a significant loss of endogenous auditory neurons. In addition, the tissue response elicited from this surgical approach was restricted to the surgical site and did not extend beyond the cochlear basal turn. Overall, this approach illustrates the feasibility of targeted cell delivery into the mammalian cochlea using hydrogel, which may be useful for future cell-based transplantation strategies, for combined treatment with a cochlear implant to restore function.
doi:10.1088/1741-2560/9/6/065001
PMCID: PMC3543852  PMID: 23186887
cochlear implant; hydrogel; stem cell; auditory neuron; deafness
5.  Neurotrophin Gene Therapy for Sustained Neural Preservation after Deafness 
PLoS ONE  2012;7(12):e52338.
The cochlear implant provides auditory cues to profoundly deaf patients by electrically stimulating the residual spiral ganglion neurons. These neurons, however, undergo progressive degeneration after hearing loss, marked initially by peripheral fibre retraction and ultimately culminating in cell death. This research aims to use gene therapy techniques to both hold and reverse this degeneration by providing a sustained and localised source of neurotrophins to the deafened cochlea. Adenoviral vectors containing green fluorescent protein, with or without neurotrophin-3 and brain derived neurotrophic factor, were injected into the lower basal turn of scala media of guinea pigs ototoxically deafened one week prior to intervention. This single injection resulted in localised and sustained gene expression, principally in the supporting cells within the organ of Corti. Guinea pigs treated with adenoviral neurotrophin-gene therapy had greater neuronal survival compared to contralateral non-treated cochleae when examined at 7 and 11 weeks post injection. Moreover; there was evidence of directed peripheral fibre regrowth towards cells expressing neurotrophin genes after both treatment periods. These data suggest that neurotrophin-gene therapy can provide sustained protection of spiral ganglion neurons and peripheral fibres after hearing loss.
doi:10.1371/journal.pone.0052338
PMCID: PMC3524079  PMID: 23284995
6.  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
7.  The effect of deafness duration on neurotrophin gene therapy for spiral ganglion neuron protection 
Hearing research  2011;278(1-2):69-76.
A cochlear implant can restore hearing function by electrically exciting spiral ganglion neurons (SGNs) in the deaf cochlea. However, following deafness SGNs undergo progressive degeneration ultimately leading to their death. One significant cause of SGN degeneration is the loss of neurotrophic support that is normally provided by cells within the organ of Corti (OC). The administration of exogenous neurotrophins (NTs) can protect SGNs from degeneration but the effects are short-lived once the source of NTs has been exhausted. NT gene therapy, whereby cells within the cochlea are transfected with genes enabling them to produce NTs, is one strategy for providing a cellular source of NTs that may provide long-term support for SGNs. As the SGNs normally innervate sensory cells within the OC, targeting residual OC cells for gene therapy in the deaf cochlea may provide a source of NTs for SGN protection and targeted regrowth of their peripheral fibers. However, the continual degeneration of the OC over extended periods of deafness may deplete the cellular targets for NT gene therapy and hence limit the effectiveness of this method in preventing SGN loss. This study examined the effects of deafness duration on the efficacy of NT gene therapy in preventing SGN loss in guinea pigs that were systemically deafened with aminoglycosides. Adenoviral vectors containing green fluorescent protein (GFP) with or without genes for Brain Derived Neurotrophic Factor (BDNF) and Neurotrophin-3 (NT3) were injected into the scala media (SM) compartment of cochleae that had been deafened for one, four or eight weeks prior to the viral injection. The results showed that viral transfection of cells within the SM was still possible even after severe degeneration of the OC. Supporting cells (pillar and Deiters' cells), cells within the stria vascularis, the spiral ligament, endosteal cells lining the scala compartments and interdental cells in the spiral limbus were transfected. However, the level of transfection was remarkably lower following longer durations of deafness. There was a significant increase in SGN survival in the entire basal turn for cochleae that received NT gene therapy compared to the untreated contralateral control cochleae for the one week deaf group. In the four week deaf group significant SGN survival was observed in the lower basal turn only. There was no increase in SGN survival for the eight week deaf group in any cochlear region. These findings indicated that the efficacy of NT gene therapy diminished with increasing durations of deafness leading to reduced benefits in terms of SGN protection. Clinically, there remains a window of opportunity in which NT gene therapy can provide ongoing trophic support for SGNs.
doi:10.1016/j.heares.2011.04.010
PMCID: PMC3152700  PMID: 21557994
Spiral ganglion neurons; gene therapy; neurotrophins; deafness; nerve protection
8.  Enhanced Auditory Neuron Survival Following Cell-Based BDNF Treatment in the Deaf Guinea Pig 
PLoS ONE  2011;6(4):e18733.
Exogenous neurotrophin delivery to the deaf cochlea can prevent deafness-induced auditory neuron degeneration, however, we have previously reported that these survival effects are rapidly lost if the treatment stops. In addition, there are concerns that current experimental techniques are not safe enough to be used clinically. Therefore, for such treatments to be clinically transferable, methods of neurotrophin treatment that are safe, biocompatible and can support long-term auditory neuron survival are necessary. Cell transplantation and gene transfer, combined with encapsulation technologies, have the potential to address these issues. This study investigated the survival-promoting effects of encapsulated BDNF over-expressing Schwann cells on auditory neurons in the deaf guinea pig. In comparison to control (empty) capsules, there was significantly greater auditory neuron survival following the cell-based BDNF treatment. Concurrent use of a cochlear implant is expected to result in even greater auditory neuron survival, and provide a clinically relevant method to support auditory neuron survival that may lead to improved speech perception and language outcomes for cochlear implant patients.
doi:10.1371/journal.pone.0018733
PMCID: PMC3078134  PMID: 21525998
9.  Meningitis after cochlear implantation 
BMJ : British Medical Journal  2007;335(7629):1058.
The risk is low, and preventive measures can reduce this further
doi:10.1136/bmj.39380.598380.80
PMCID: PMC2094185  PMID: 18033888
10.  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
11.  A PROTOCOL FOR CRYOEMBEDDING THE ADULT GUINEA PIG COCHLEA FOR FLUORESCENCE IMMUNOHISTOLOGY 
Journal of neuroscience methods  2008;176(2):144-151.
Green fluorescent protein (GFP) has been used extensively to label cells in vitro and to track them following their transplantation in vivo. During our studies using the mouse embryonic stem cell line R1 B5-EGFP, we observed variable levels of fluorescence intensity of the GFP within these transfected cells. The variable fluorescence of this protein coupled with the innately autofluorescent nature of several structures within the cochlea collectively made the in vivo identification of these transplanted stem cells difficult. We have modified previously published protocols to enable the discrimination of an authentic GFP signal from autofluorescence in the adult guinea pig cochlea using fluorescence-based immunohistochemistry. The protocol described can also be used to label tissues of the cochlea using a chromogen, such as 3,3′-diaminobenzidine tetrahydrochloride (DAB). Moreover, the described method gives excellent preservation of structural morphology making the tissues useful for both morphological and quantitative studies in combination with robust immunohistochemistry in the adult guinea pig cochlea.
doi:10.1016/j.jneumeth.2008.09.007
PMCID: PMC2935960  PMID: 18835298
Cochlea; stem cells; GFP; cryosectioning; cell transplantation; deafness
12.  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
13.  Bilateral cochlear implantation in the ferret: A novel animal model for behavioral studies 
Journal of Neuroscience Methods  2010;190(2):214-228.
Bilateral cochlear implantation has recently been introduced with the aim of improving both speech perception in background noise and sound localization. Although evidence suggests that binaural perception is possible with two cochlear implants, results in humans are variable. To explore potential contributing factors to these variable outcomes, we have developed a behavioral animal model of bilateral cochlear implantation in a novel species, the ferret. Although ferrets are ideally suited to psychophysical and physiological assessments of binaural hearing, cochlear implantation has not been previously described in this species. This paper describes the techniques of deafening with aminoglycoside administration, surgical implantation of an intracochlear array and chronic intracochlear electrical stimulation with monitoring for electrode integrity and efficacy of stimulation. Experiments have been presented elsewhere to show that the model can be used to study behavioral and electrophysiological measures of binaural hearing in chronically implanted animals. This paper demonstrates that cochlear implantation and chronic intracochlear electrical stimulation are both safe and effective in ferrets, opening up the possibility of using this model to study potential protective effects of bilateral cochlear implantation on the developing central auditory pathway. Since ferrets can be used to assess psychophysical and physiological aspects of hearing along with the structure of the auditory pathway in the same animals, we anticipate that this model will help develop novel neuroprosthetic therapies for use in humans.
doi:10.1016/j.jneumeth.2010.05.014
PMCID: PMC2938482  PMID: 20576507
Cochlear implant; Ferret; Binaural hearing; Bilateral cochlear implantation; Deafness; Neural prosthesis; Hearing loss; Spatial hearing
14.  Schwann cells genetically modified to express neurotrophins promote spiral ganglion neuron survival in vitro 
Neuroscience  2008;152(3):821-828.
The intracochlear infusion of neurotrophic factors via a mini-osmotic pump has been shown to prevent deafness-induced spiral ganglion neuron (SGN) degeneration; however, the use of pumps may increase the incidence of infection within the cochlea, making this technique unsuitable for neurotrophin administration in a clinical setting. Cell- and gene-based therapies are potential therapeutic options. This study investigated whether Schwann cells which were genetically modified to over-express the neurotrophins brain-derived neurotrophic factor (BDNF) or neurotrophin 3 (Ntf3, formerly NT-3) could support SGN survival in an in vitro model of deafness. Co-culture of either BDNF over-expressing Schwann cells or Ntf3 over-expressing Schwann cells with SGNs from early postnatal rats significantly enhanced neuronal survival in comparison to both control Schwann cells and conventional recombinant neurotrophin proteins. Transplantation of neurotrophin over-expressing Schwann cells into the cochlea may provide an alternative means of delivering neurotrophic factors to the deaf cochlea for therapeutic purposes.
doi:10.1016/j.neuroscience.2007.11.057
PMCID: PMC2726277  PMID: 18304740
auditory; ex vivo gene transfer; BDNF; Ntf3
15.  Cochlear Implants Stimulate Activity-Dependent CREB Pathway in the Deaf Auditory Cortex: Implications for Molecular Plasticity Induced by Neural Prosthetic Devices 
Cerebral Cortex (New York, NY)  2007;18(8):1799-1813.
Neural activity modulates the maturation of synapses and their organization into functional circuits by regulating activity-dependent signaling pathways. Phosphorylation of cyclic AMP/Ca2+-responsive element-binding protein (CREB) is widely accepted as a stimulus-inducible event driven by calcium influx into depolarized neurons. In turn, phosphorylated CREB (pCREB) activates the transcription of brain-derived neurotrophic factor (BDNF), which is needed for synaptic transmission and long-term potentiation. We examined how these molecular events are influenced by sensorineural hearing loss and long-term reactivation via cochlear implants. Sensorineural hearing loss reduced the expression of pCREB and BDNF. In contrast, deafened animals subject to long-term, unilateral intracochlear electrical stimulation exhibited an increased expression of pCREB and BDNF in the contralateral auditory cortical neurons, relative to ipsilateral ones. These changes induced by cochlear implants are further accompanied by the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which has been implicated in long-lasting forms of synaptic plasticity. Because CREB and BDNF are critical modulators of synaptic plasticity, our data describe for the first time possible molecular candidate genes, which are altered in the auditory cortex, following cochlear implantation. These findings provide insights into adaptive, molecular mechanisms recruited by the brain upon functional electrical stimulation by neural prosthetic devices.
doi:10.1093/cercor/bhm206
PMCID: PMC2790391  PMID: 18063565
activity-dependent gene; BDNF; electrical stimulation; MAPK; sensorineural hearing loss; synaptic plasticity
16.  Neurotrophins and electrical stimulation for protection and repair of spiral ganglion neurons following sensorineural hearing loss 
Hearing research  2007;242(1-2):100-109.
Exogenous neurotrophins (NTs) have been shown to rescue spiral ganglion neurons (SGNs) from degeneration following a sensorineural hearing loss (SNHL). Furthermore, chronic electrical stimulation (ES) has been shown to retard SGN degeneration in some studies but not others. Since there is evidence of even greater SGN rescue when NT administration is combined with ES, we examined whether chronic ES can maintain SGN survival long after cessation of NT delivery. Young adult guinea pigs were profoundly deafened using ototoxic drugs; five days later they were unilaterally implanted with an electrode array and drug delivery system. Brain derived neurotrophic factor (BDNF) was continuously delivered to the scala tympani over a four week period while the animal simultaneously received ES via bipolar electrodes in the basal turn (i.e. turn 1) scala tympani. One cohort (n=5) received ES for six weeks (i.e. including a two week period after the cessation of BDNF delivery; ES6); a second cohort (n=5) received ES for 10 weeks (i.e. a six week period following cessation of BDNF delivery; ES10). The cochleae were harvested for histology and SGN density determined for each cochlear turn for comparison with normal hearing controls (n=4). The withdrawal of BDNF resulted in a rapid loss of SGNs in turns 2–4 of the deafened/BDNF-treated cochleae; this was significant as early as two weeks following removal of the NT when compared with normal controls (p<0.05). Importantly, there was not a significant reduction in SGNs in turn 1 (i.e. adjacent to the electrode array) two and six weeks after NT removal, as compared with normal controls. This result suggests that chronic ES can prevent the rapid loss of SGNs that occurs after the withdrawal of exogenous NTs. Implications for the clinical delivery of NTs are discussed.
doi:10.1016/j.heares.2007.12.005
PMCID: PMC2630855  PMID: 18243608
neural degeneration; neurotrophin; deafness; electrical stimulation; cochlear implant; neural prostheses
17.  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
18.  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
19.  A fully implantable stimulator for use in small laboratory animals 
Journal of neuroscience methods  2007;166(2):168-177.
This paper describes a low cost, fully implantable, single channel stimulator that can be manufactured in a research laboratory. The stimulator generates charge-balanced biphasic current pulses which are delivered to a bipolar electrode array for chronic stimulation of neural tissue in free-running laboratory animals such as rats and mice. The system is magnetically coupled and contains no batteries or external leadwires. The subject is placed in a chamber surrounded by three orthogonal coils of wire which are driven to generate a magnetic field. Currents are induced in wire coils in the implanted stimulator then regulated to produce biphasic current pulses with fixed amplitude of up to 500 μA. Phase duration is adjustable from 25 – 250 μs per phase. Charge balance is maintained by capacitive coupling and shorting of the electrodes between pulses. Stimulus rate can be continuously varied, and the temporal precision of the stimulus means that the stimulator can be used in behavioural experiments or for generating electrically-evoked potentials. We describe the application of this stimulator for chronic electrical stimulation of the auditory nerve (i.e. a cochlear implant); however it will have application in other areas of neuroscience requiring controlled safe electrical stimulation of neural tissue over extended periods. Circuit diagrams and manufacturing details are provided as supplementary data.
doi:10.1016/j.jneumeth.2007.07.009
PMCID: PMC2001238  PMID: 17897719
electrical stimulation; cochlear implant; neural prostheses; stimulator; mouse
20.  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
21.  Threshold shift: effects of cochlear implantation on the risk of pneumococcal meningitis 
Objectives
To examine whether cochlear implantation increases the risk of meningitis in the absence of other risk factors, and to understand the pathogenesis of pneumococcal meningitis post cochlear implantation.
Study Design and Setting
A quantitative threshold model in rats was established to examine how the presence of a cochlear implant and surgical insertion trauma alter the risk of pneumococcal meningitis post implantation from all potential routes of infection from the upper respiratory mucosa to the meninges.
Results
The presence of a cochlear implant reduced the threshold of bacteria required to cause pneumococcal meningitis from all routes of infection (hematogenous, the middle ear and inner ear) in healthy animals. Mild electrode insertion trauma did not alter the threshold of infection.
Conclusion
Our animal model has demonstrated that cochlear implantation is an independent risk factor for pneumococcal meningitis. The presence of a foreign body such as a cochlear implant increases the risk of pneumococcal meningitis regardless of the routes of bacterial infection.
Significance
Early detection and treatment of pneumococcal infection such as otitis media may be required in implant recipients as the experimental data suggest that the cochlear implantation leads to a reduction of threshold for meningitis.
doi:10.1016/j.otohns.2006.11.039
PMCID: PMC1852444  PMID: 17418257
22.  Exogenous BDNF rescues rat spiral ganglion neurons in vivo 
The loss of hair cells resulting in a sensorineural hearing loss (SNHL) also leads to the secondary degeneration of spiral ganglion neurons (SGNs). The effectiveness of cochlear implantation in patients with a profound SNHL relies, in part, upon the survival of SGNs; therefore any therapy that can prevent or halt the loss of these neurons would be of potential clinical benefit. Previous research has shown that intracochlear infusion with neurotrophins can provide trophic support to SGNs in deafened guinea pigs. It remains to be determined whether this effect is seen in other species. After documenting the rate of SGN degeneration following ototoxic deafening, we investigated the trophic effects of exogenous brain-derived neurotrophic factor (BDNF) on rat SGNs. The left cochleae of profoundly deafened rats were implanted with a drug delivery system connected to a mini-osmotic pump. BDNF or artificial perilymph (AP) was infused for 28 days and the cochleae were then prepared for histology. Treatment with BDNF led to a statistically significant increase in SGN density and a highly significant increase in SGN soma area compared to AP-treated and untreated deafened cochleae. This work has demonstrated the trophic advantage of exogenous BDNF in the mature rat cochlea and provides confidence that SGN rescue following SNHL with exogenous BDNF may have clinical application.
PMCID: PMC1851892  PMID: 16151360
Neural degeneration; neurotrophin; deafness; ototoxicity; cochlear implant
23.  Pneumococcal meningitis threshold model: a potential tool to assess infectious risk of new or existing inner ear surgical interventions 
Hypothesis
A minimal threshold of S. pneumoniae is required to induce meningitis in healthy animals for intraperitoneal (hematogenous), middle ear and inner ear inoculations and this threshold may be altered by recent inner ear surgery.
Background
There has been an increase in the number of reported cases of cochlear implant-related pneumococcal meningitis since 2002. The pathogenesis of pneumococcal meningitis is complex and not completely understood. The bacteria can reach the central nervous system (CNS) from the upper respiratory tract mucosa via either hematogenous route or via the inner ear. The establishment of a threshold model for all potential routes of infection to the CNS in animals without cochlear implantation is an important first step to help us understand the pathogenesis of the disease in animals with cochlear implantation.
Methods
54 otologically normal, adult Hooded Wistar rats (27 receiving cochleostomy and 27 controls) were inoculated with different amounts of bacterial counts via three different routes (intraperitoneal, middle ear and inner ear). Rats were monitored over 5 days for signs of meningitis. Blood, CSF and middle ear swabs were taken for bacterial culture and brains and cochleae were examined for signs of infection.
Results
The threshold of bacterial counts required to induce meningitis is lowest in rats receiving direct inner ear inoculation compared to both intraperitoneal and middle ear inoculation. There is no change in threshold between the group of rats with cochleostomy and the control (Fisher exact test; p < 0.05).
Conclusion
A minimal threshold of bacteria is required to induce meningitis in healthy animals and is different for three different routes of infection (intraperitoneal, middle ear and inner ear). Cochleostomy performed 4 weeks prior to the inoculation did not reduce the threshold of bacteria required for meningitis in all three infectious routes. This threshold model will also serve as a valuable tool, assisting clinicians to quantitatively determine if the presence of a cochlear implant or other central nervous system (CNS) prostheses alter the risk of meningitis.
doi:10.1097/01.mao.0000227898.80656.54
PMCID: PMC1847393  PMID: 16980916
pneumococcal meningitis; routes of infection; Streptococcus pneumoniae; threshold model
24.  Effects of inner ear trauma on the risk of pneumococcal meningitis 
Objectives
To examine the risk of pneumococcal meningitis in healthy rats that received either a severe surgical trauma to the modiolus and osseous spiral lamina or the standard insertion technique for acute cochlear implantation.
Designs
Interventional animal studies.
Subjects
54 otologically normal, adult, Hooded Wistar rats.
Interventions
54 rats (18 which received a cochleostomy alone, 18 which received a cochleostomy and acute cochlear implantation using standard surgical techniques, and 18 which received a cochleostomy followed by severe inner ear trauma) were infected four weeks following surgery with S. pneumoniae via three different routes (hematogenous, middle ear and inner ear) to represent all potential routes of bacterial infection from the upper respiratory tract to the meninges in cochlear implant recipients with meningitis.
Results
Severe trauma to the osseous spiral lamina and modiolus increased the risk of pneumococcal meningitis when the bacteria were given via the middle or inner ear (Fisher’s exact test P<0.05). However, the risk of meningitis did not change when the bacteria were given via the hematogenous route. Acute electrode insertion did not alter the risk of subsequent pneumococcal meningitis for any route of infection.
Conclusion
Severe inner ear surgical trauma to the osseous spiral lamina and modiolus can increase the risk of pneumococcal meningitis. Therefore every effort should be made to ensure that cochlear implant design and insertion technique cause minimal trauma to the bony structures of the inner ear in order to reduce the risk of pneumococcal meningitis.
doi:10.1001/archotol.133.3.250
PMCID: PMC1840049  PMID: 17372082
25.  Protective effects of local administration of ciprofloxacin on the risk of pneumococcal meningitis following cochlear implantation 
The Laryngoscope  2006;116(12):2138-2144.
Objectives
To determine if ciprofloxacin retains its antimicrobial activity after storage with Healon® at ambient temperature and at 37°C over 5 weeks and then to establish whether the application of ciprofloxacin/Healon® onto scala tympani electrode arrays reduces the risk of meningitis in implanted rats inoculated with S. pneumoniae.
Study design
in vitro laboratory and in vivo animal studies
Methods
The antibacterial activity of three concentrations of ciprofloxacin/Healon® (7.5, 75 and 750 μg/ml) was examined over 5 weeks at both ambient temperature (23°C) and body temperature (37°C). Thirty-six rats (18 implanted with ciprofloxacin (750 mg/ml)/Healon®-coated electrode array and 18 without the coating) were infected with S. pneumoniae 4 weeks after implantation via three different routes of infection (hematogenous, middle ear and inner ear) and observed for the development of meningitis.
Results
The antibacterial activity of ciprofloxacin/Healon® was maintained over 5 weeks at both 23°C and 37°C. The implanted rats with the ciprofloxacin/Healon-coated electrode array were protected from meningitis when the bacteria were given via the hematogenous route (Fisher’s exact test P =0.008, but not when the bacteria were inoculated directly into the middle or inner ear. However, the time to develop meningitis was significantly longer in rats implanted with a coated array, irrespective of the route of inoculation (P <0.05, log rank test).
Conclusion
Our animal model demonstrated that a ciprofloxacin-coated electrode array can protect healthy implanted rats from meningitis when the route of infection is hematogenous, and can delay the onset of meningitis when bacteria are inoculated directly into the middle or inner ear.
doi:10.1097/01.mlg.0000243192.43574.81
PMCID: PMC1839843  PMID: 17146386
Ciprofloxacin; Sodium hyaluronate; pneumococcal meningitis; cochlear implantation; Streptococcus pneumoniae

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