at the forefront of to a bionic era. international medical · temporary hearing loss, and ringing...

12013 Bionics Institute Research Report

2013 Research Report

From the bionic ear to a bionic era.At the forefront of

international medical bionic device research.

02 Director’s Report

03 Bionic Hearing

13 Bionic Vision

19 Neurobionics

25 Publications

Contents


Professor Robert K Shepherd BSc, DipEd, PhD

Director

Director’s ReportExpansion, innovation and outcomes are the words that best describe 2013 for the Bionics Institute. Over the year the organisation delivered results across our three core research themes. In collaboration with our Bionic Vision Australia partners we showed that patterns recognisable as letters and numbers can be produced by stimulating multiple electrodes and we examined ways to increase the number of effective electrodes in the bionic eye. These are just two examples of our success.

Through bionic hearing and our emerging research in neurobionics the Institute took great strides both in pushing the boundaries of knowledge and developing new techniques that will be critical to the treatment of patients. An example is the development of an objective measure of tremor in Parkinson’s disease patients where previously subjective measurements existed. This measure is being used to optimise the stimulation parameters in patients with a deep brain stimulation device so that they receive optimal symptom relief. Another clinical benefit of this measure is that it can be used to more accurately tailor a drug treatment regimen to an individual patient thereby enhancing the longevity of drug treatments.

None of this excellent work would be possible without the right research skills. Over the past 12 months the Institute has recruited a number of exceptional researchers who work alongside our highly-dedicated team. Of particular note is the veski senior innovation research fellow, Professor Colette McKay, who returned to Australia and the Bionics Institute in 2013 to lead the clinical research in our hearing team. Professor McKay is bringing exciting research back to Australia including methods to automatically set safe and comfortable stimulation levels for cochlear implant patients. This is of particular value to very young implant recipients what are unable to communicate if their implant is set too loud or too soft.

We are also proud of our PhD research students who continue to make a significant contribution to the Institute. Through 2013 our senior researchers supervised 19 PhD students, three submitted their theses and Dr Sam John graduated.

The Institute’s collaborative links remain crucial to our success and it is important to recognise our affiliations with Melbourne’s Eastern Hill precinct, encompassing two internationally regarded teaching hospitals - the Royal Victorian Eye and Ear Hospital and St Vincent’s Hospital. Our research teams work closely with colleagues at both institutions and this extends to affiliations within the Faculty of Medicine, Dentistry and Health Sciences and the School of Engineering at the University of Melbourne. We are also a proud member of the Aikenhead Centre for Medical Discovery on the St Vincent’s campus.

We acknowledge the vital support we receive from the Victorian Government through its Operational Infrastructure Support Program, as well as key Federal Government funding through the Australian Research Council and the National Health and Medical Research Council.

We are very grateful for the generous commitment of trusts and foundations that have provided a crucial source of research funding for the Institute. We would particularly like to acknowledge the support we receive from the Victorian Lions Foundation through their continued funding

of the Lions International Hearing Research Fellow and their recent commitment to a Neurobionics Research Fellow, the Garnett Passe and Rodney Williams Memorial Foundation for funding our advanced cochlear implant research, and the Colonial Foundation for its support of our neurobionics research program.

Professor Robert K Shepherd BSc, DipEd, PhD Director

3 2013 Bionics Institute Research Report

The cochlear implant is a biomedical success story, but the current device has limitations. Our bionic hearing program aims to improve the quality of hearing provided by cochlear implants and hearing aids and encompasses: the development of new strategies to improve the perception of speech and music; auditory neuroscience to understand how the brain responds to electrical stimulation of the cochlea; and the investigation of techniques to rescue the hearing nerve from degeneration.

During the past year our researchers have:

— Carried out studies to test a new cochlear implant stimulation strategy that focusses electrical current onto smaller regions of the cochlea with the aim of conveying more precise and clearer sounds

— Worked on new sound presentation and training methods to improve the perception and appreciation of music by cochlear implant recipients

— Examined how the brain’s plasticity enables listeners to adapt to combined acoustic and electrical stimulation of the cochlea

— Examined the possibility of using infrared light combined with electrical stimulation to activate the auditory nerve

— Investigated gene therapy as a means of regenerating sensory (hair) cells in the deaf cochlea

— Investigated several methods for introducing survival factors into the cochlea to protect the hearing nerve from degeneration

— Commenced a study to explore a new way of treating Ménière’s disease, a debilitating condition that causes dizziness, hearing loss, and ringing in the ears.

Bionic Hearing

PROJECTS:

Electro-acoustic hearingCochlear implants were initially provided only to patients with no usable hearing in either ear. However, both children and adults with useful amounts of low-frequency hearing (i.e. severe mid to high frequency hearing loss) are now routinely implanted.

Cochlear implant recipients with some residual hearing have access to information from acoustic hearing (via their remaining low-frequency hearing) and electric hearing (via their cochlear implant that stimulates the high-frequency regions of the cochlea). The current clinical focus is on: who are the most appropriate candidates for electro-acoustic stimulation; the procedures to fit the implants for optimal performance with electro-acoustic stimulation for each individual; and the best way to preserve as much of the existing hearing as possible. However, there is very little known about how the two modalities are represented and integrated in the central auditory pathway or the effects of long-term partial deafness and chronic electrical and acoustic stimulation on these processes.

We are investigating the effects of long-term partial deafness, either from a young age or in later life, and chronic electrical and acoustic stimulation on the way in which stimuli to acoustic and electrical hearing are represented and integrated in primary auditory cortex.

In the past year we have:

— Successfully developed a model depicting interaction of partial hearing and cochlear implantation

— Found cochlear implant use results in a decrease in acoustically responsive locations in the primary auditory cortex

— Found the interaction between acoustic and electric stimulation has a complex dependence on intensity and frequency.

The mean auditory brainstem response audiograms for the three groups, neonatally deafened unstimulated (red), neonatally deafened stimulated (green) and adult deafened stimulated (black), and the 95% confidence interval for normal hearing animals (grey shaded region, n = 10).



— Developed a novel combined electro-optical array that allows us to stimulate the cochlea with both optical and electrical stimulation simultaneously

— Used the combined array to successfully activate the auditory pathway in normal hearing animals

— Shown that combined stimulation appears to produce a small, but statistically significant, reduction in auditory nerve activation threshold compared to electrical stimulation alone.

Research Team: Prof Rob Shepherd, Dr James Fallon, Dr Andrew Wise, Ms Amy Morley, and Ms Nicole Critch.

External collaborators: A/Prof Paul Stoddart, Dr Scott Wade, and Mr Alex Thompson (Swinburne University of Technology); and Dr Natalie James (Cochlear Ltd, The University of Sydney).

Funding: ARC Linkage Grant.

Novel electrical stimulation methods for improved cochlear implant sound processing: preclinical studiesCochlear implants electrically stimulate the auditory nerve in order to convey frequency (spectral) and timing (temporal) information to severe-to-profoundly deaf patients. While cochlear implant users typically receive significant benefit in understanding speech under quiet conditions, performance drops significantly with noise. Moreover, contemporary

stimulation strategies do not convey the rich aural texture of music or tonal languages effectively.

In principle, electrical stimulation of a single electrode site with a temporally modulated signal will excite a single cochlear place, giving rise to a unique pitch percept with the same temporal structure as the electrical stimulus. In practice, however, neural excitation is spatially very broad due to the conductive nature of the inner ear fluids. As a consequence, the stimulating channels overlap considerably so that any one auditory neuron can be activated by multiple electrodes.

This study aims to examine the effectiveness of a current focusing technique (termed phased array stimulation) designed to provide spatially precise, temporally independent sites of cochlear activation for improved sound processing in cochlear implants.

To date, numerous experiments have been successfully completed in short and long-term models, in which recordings have been taken from the auditory midbrain (inferior colliculus) in response to pure tones. Results have shown that when the pure tune frequency increases, deeper sites of the inferior colliculus are activated. We are currently seeking to develop procedures for the simultaneous stimulation of auditory neurones.


— Completed a custom built stimulator capable of delivering focussed stimulation

— Found that phased array stimulation can produce more restricted activation of the auditory pathway

— Shown that thresholds for phased array stimulation are higher than conventional (monopolar) stimulation.

Research Team: Dr James Fallon, Dr Sam Irving, Prof Dexter Irvine, Prof Hugh McDermott, Ms Alison Evans, Ms Nicole Critch, Ms Amy Morley, Dr Andrew Wise, Mr Rodney Millard, Ms Helen Feng and Prof Rob Shepherd.

Funding: NHMRC project grant.

Optical-Electrical Co-stimulation of Auditory NeuronsTraditionally, cochlear implants have operated by electrically stimulating auditory neurons inside the cochlea. Neuron stimulation via infrared light is an attractive alternative approach since it may be less invasive and better able to target small groups of neurons, thereby leading to enhanced sound perception. However, in the case of cochlear implants, optical stimulation alone is too power hungry to be competitive with current electrode array technologies. Recently it has been suggested that electrical stimulation can be used to reduce the optical stimulation threshold. This suggests that the best features of the two techniques may be obtained through a combined stimulation approach. Therefore we aim to establish the feasibility of combining electrical and optical stimulation by investigating the underlying biophysical mechanisms and physiological effects in the auditory nerves.

The proportion of units responsive to different modes of stimulation (only electric, solid; only acoustic, clear; both, stripe) for neonatally deafened unstimulated (NDU), neonatally deafened stimulated (NDS) and adult deafened stimulated (ADS) groups.

New array developed for combined optical and electrical stimulation of the cochlea.


Research Team: Prof Rob Shepherd, Dr James Fallon, Dr Andrew Wise, Ms Shefin George, Mr Philipp Senn, Ms Melanie Gault, Ms Alison Neil, Ms Amy Morley, Ms Nicole Critch, and Mr Damian Robb.

Components of this work are the subject of PhD research by Ms Shefin George who was/is supported by a Bart Reardon Scholarship and an Australian Postgraduate Award.

External collaborators: Dr Zach Smith, Dr Stoph Long, and Mr Shaun Kumar (Cochlear Ltd).

Funding: Garnett Passe and Rodney Williams Memorial Foundation.

Watching the brain reorganiseIn normal hearing people and animals, the auditory cortex of the brain is spatially organised according to sound frequency. The auditory brain of profoundly deaf individuals loses this typical cochleotopic organisation. Our previous work has shown that the use of a cochlear implant, from either a young age or later in life, can rectify many of the changes in cortical organisation that occur after long periods of deafness and can

Bionic Hearing

Inferior colliculus (IC) response images of various electrode configurations. Each image is labelled according to configuration and channel number. Warmer colours indicate a stronger response. Monopolar stimulation (MP) evokes a broad area of excitation. In contrast current focusing stimulation (FMP) produces a far more localised excitation pattern.

The spread of excitation (measured as the spatial tuning curve (STC) width) is significantly narrower to the current focusing stimulation (green) compared to monopolar stimulation (blue).

these neurons process the novel signals arising from the cochlear implant

— Chronic stimulation using a cochlear implant causes changes in cortical organisation in the deaf brain after as little as two months stimulation. However, in some individuals, this organisation can appear at later time points and may not appear at all.

These results will help us to understand how the cochlear implant is interacting with the brain, and will allow us to tailor stimulation methods and rehabilitation to capitalise on these interactions.

Research Team: Dr James Fallon, Dr Sam Irving, Prof Dexter Irvine, Prof Rob Shepherd, Dr Andrew Wise, Ms Alison Neil, Ms Amy Morley, and Ms Nicole Critch.

Funding: NHMRC; National Institutes of Health, USA (NIDCD (HHS-N-263-2007-00053-C).

New methods forevaluating the performance of cochlear implants

restore near normal organisation in some cases.

Our current investigation uses state-of-the-art chronic stimulation (via a cochlear implant) and brain recording techniques to determine the time period over which the cortical organisation can be recovered.

In the past year we have shown:

— Chronic use of a cochlear implant causes activation of previously unresponsive neurons in the deaf auditory cortex, and

A) Mean correlation of cortical response compared to cochlear position, indicating that the auditory cortex becomes increasingly organised with chronic stimulation. B) Example of best electrode vs. caudal-rostral position in auditory cortex showing no organisation in the initial session and significant stimulus-driven cochleotopic organisation of auditory cortex after 5 months of stimulation. Pearson’s r and p values are inset.


The use of behavioural animal models in hearing research has led to an understanding of some fundamental questions regarding mammalian hearing, which contributed to the advancement of cochlear implants (CI). As more people with partial hearing loss receive cochlear implants, more questions emerge regarding combined electric and acoustic sound perception. To answer these emerging questions a behavioural animal model is required. The aim of this study was to determine the behavioural frequency discrimination ability in partially deafened animals using a CI.

Animals with a high frequency hearing loss (7 kHz cutoff) were implanted with customised CIs. All animals were trained on a go/no-go, positive reinforcement, frequency discrimination task and reached asymptotic performance (measured by d’ - detection theory) before starting the experiment. Throughout 6-9 months of continuous performance measurement, the CI stimulator was turned off 1-2 times for one month. Reference frequencies (1, 4, and 7 kHz) were systematically rotated (Latin Square design) every 9-11 days to cover the hearing range of the animals while avoiding bias arising from the order of testing.

Typical learning curve (animal B1) over the first 45 days. (A) Trials per day throughout the 45 day period. (B) Green plus signs and red crosses represent hit and FA (false alarm) rate, respectively, which were calculated using 100-trial windows. (C) Variation in d-prime (d’) over training period. Dashed line represents 3-point interpolation.

Chronic implantation of encapsulated BDNF-fibroblasts elicited minimal adverse or inflammatory reactions in the deaf cochleav. The alginate membrane of two capsules (arrows), as well as a cluster of encapsulated cells (*) can be seen. ST: scala tympani.

We found significant improvement in behavioural performance for two (1 and 7 kHz) out of three reference frequencies when the CI stimulator was turned on. Overall, subjects performed the frequency discrimination task significantly better with a CI turned on compared to the off condition (3-way ANOVA, p<0.001). The analysis also showed no dependence on subject (3-way ANOVA, subject x on-off condition, p>0.5) but significant dependence on the reference frequency (3-way ANOVA, reference frequency x on-off condition, p<0.03).

In the past year we showed:

— Performance on an acoustic frequency discrimination task is stable and repeatable over time

— For the first time, animals can utilize information provided by CI electric stimulation in performing a behavioural frequency discrimination task

— Subjects performed the frequency discrimination task significantly better with a cochlear implant turned on compared to the off condition.

Research team: Yuri Benovitski (PhD student), Prof Peter Blamey, Mr Graeme Rathbone and Dr James Fallon.

Funding: La Trobe University Full Fee Remission Scholarship and La Trobe University Postgraduate Research Scholarship to Mr Yuri Benovitski.

Cell-based neurotrophin treatment for auditory neuron survival

The cochlear implant provides auditory cues to patients with a profound sensorineural hearing loss by electrically stimulating the auditory neurons of the cochlea. However, auditory neurons degenerate in deafness, which may limit the efficacy of the cochlear implant. Cell-based therapies are a potentially viable method for delivering nerve survival factors, known as neurotrophins, to the deaf cochlea to prevent auditory neuron degeneration.

We aim to preserve auditory neuron survival in deafness using (a) long-term cell-based neurotrophin delivery and (b) cell-based neurotrophin treatment in conjunction with chronic electrical stimulation from a cochlear implant. This project uses cells that secrete a specific neurotrophin known as BDNF, and we encased the cells in a specialised capsule to prevent migration and minimise immune responses.

Cell-based neurotrophin treatment elicits long-term survival effects on auditory neurons in the deaf cochlea. The implantation of encapsulated BDNF-fibroblasts resulted in enhanced auditory neuron survival in comparison to empty (control) capsules for at least six months post-implantation.


Bionic Hearingauditory nerve endings are located. We examined neurotrophin genes called Ntf-3 and BDNF for nerve survival and a gene called Atoh1 for hair cell regeneration.

Neurotrophin gene therapy in the sensory region of the cochlea protected auditory neurons from degeneration for 6 months, a timeline that is equivalent to many years in humans. However, the gene therapy did not prevent the overall degeneration of the sensory region and eventually the protective genes were lost. Targeting gene therapy to cells that do not degenerate after hearing loss would be required to increase the period of neural protection. Atoh1 gene therapy enabled residual supporting cells in the sensory region to assume characteristics of hair cells as assessed by numerous molecular markers. The hair cells were considered immature hair cells as they did not express mature hair cell markers and they did not reconnect to nearby auditory neurons.


— Atoh1 gene therapy resulted in new immature hair cells via transformation of residual supporting cells. However, hearing was not restored suggesting that an additional step is required to functionally reconnect the cochlea after hearing loss.

— Localised cochlear neurotrophin gene therapy protected auditory neurons after profound hearing loss. Significant and long-term neural survival was found in the high frequency region of the

cochlea near regions of neurotrophin gene expression.

This study is a first but important step in regenerating and reconnecting the cochlea after sensorineural hearing loss.

Research Team: Dr Rachael Richardson, Dr Andrew Wise, Mr Patrick Atkinson and Ms Brianna Flynn.

Components of this work are the subject of PhD research by Mr Patrick Atkinson who is supported by a Garnett Passe and Rodney Williams Memorial Foundation Scholarship.

External collaborators: Prof Stephen O’Leary (University of Melbourne); and Prof Cliff Hume (University of Washington).

Funding: Garnett Passe and Rodney Williams Memorial Foundation; Action on Hearing Loss.

Gene therapy for preventing progressive sensorineural hearing loss and restoring hearingMany forms of hearing loss result in the degeneration of the cochlea’s sensory cells (hair) cells, their supporting cells, and the auditory nerves. We have previously shown that neurotrophin gene therapy in the cochlea can protect auditory neurons from degeneration after a rapid and severe form of deafness (ototoxicity). In this project we

(a) Top-down view of inner and outer hair cells (IHC; OHC; red) in a normal cochlea with cell nuclei labelled in blue. (b) Regenerated hair cells (red) in a profoundly deaf cochlea treated with Atoh1 gene therapy (green cells). Residual supporting cells have been converted to cells with the phenotype of hair cells. These cells are often found in the inner hair cell location of the sensory region. Cell nuclei are labelled in blue. Scale bars are 20 μm.


— Cell-based neurotrophin treatment of the deaf cochlea enhances auditory neuron survival for at least six months, and the survival effects have associated functional benefits

— Combined treatment with cell-based neurotrophin treatment and concurrent electrical stimulation supports auditory neuron survival and has associated functional benefits

— Chronic implantation of these encapsulated cells into the cochlea caused minimal immune and inflammatory reactions, indicating that the implanted cells were biocompatible and well tolerated.

Cell-based neurotrophin treatment therefore presents a clinically relevant method to support long-term auditory neuron survival in deafness, which in turn may improve the efficacy of the cochlear implant and lead to improved speech perception and language outcomes for cochlear implant patients.

Research Team: Dr Lisa Gillespie, Prof Rob Shepherd, Ms Amy Morley, and Ms Nicole Critch.

External collaborators: Professor Alan Harvey (University of Western Australia), Professor Dwaine Emerich (InCytu, Rhode Island, USA) and Dr Chris Thanos (Cytosolv, Rhode Island, USA).

Funding: Garnett Passe and Rodney Williams Memorial Foundation; NHMRC.

Protecting and restoring cochlear sensory cells with targeted gene therapyIrreversible sensorineural hearing loss results from the damage or loss of the cochlea’s sensory (hair) cells and/or hearing nerves. Currently, the only clinical option for people with severe to profound sensorineural hearing loss is a cochlear implant. Emerging gene therapies however, may enable the replacement or repair of hair cells and auditory nerves for the restoration of hearing. Our group used a gene therapy technique that targets the sensory region of the cochlea where the hair cells and


sought to determine if we could also protect cochlear hair cells with gene therapy by utilising a form of hearing loss in which the sensory cells degenerate at a slower pace, namely noise-induced hearing loss. This type of hearing loss resulted in a notch of hair cell loss. In general, with gene therapy, protected and regenerated hair cells were observed within this damaged region in greater numbers compared to control gene therapy.

Our studies involved providing localised cochlear gene therapy to a model with a high frequency noise-induced hearing loss. The brain-derived neurotrophic factor (BDNF) gene was tested for hair cell protection and the Atoh1 gene was trialled for hair cell regeneration. After 3 weeks it was shown that there were greater numbers of hair cells in the noise-damaged regions of the model cochleae treated with BDNF or Atoh1 compared to control groups. The majority of these hair cells co-localised with cells expressing the transgenes. However, synaptic proteins were not expressed in the protected or transformed hair cells. Furthermore, gene therapy with either gene did not protect or restore hearing suggesting that further protective or transforming steps are required for the maintenance or formation of mature hair cells with functional connections.


— Developed a progressive noise-induced hearing loss animal model to enable hair cell protection and hair cell regeneration studies

— Shown protection of hair cells after noise-induced hearing loss with localised neurotrophin gene therapy in the cochlea

— Shown the transformation of residual cells in the cochlea into new hair cells by Atoh1 gene therapy after noise-induced hearing loss; however hearing was not restored.

Research Team: Dr Rachael Richardson, Dr Andrew Wise, Mr Patrick Atkinson, and Ms Brianna Flynn.

External collaborators: Prof Stephen O’Leary (University of Melbourne); and Dr Liang-Fong Wong (University of Bristol).

Funding: NHMRC.

A drug-delivery system for nerve survival factors in the inner ear using nanotechnologyThe delicate sensory cells in the cochlea are very sensitive to trauma such as loud noise, some anti-cancer drugs and a certain class of antibiotics used to fight infection. When the sensory cells die, the auditory neurons that make connections with them also die. The auditory neurons are the target of a cochlear implant, which works by electrically stimulating the neurons to effectively bypass the lost sensory cells. Institute researchers have shown that by administering a nerve survival factor (called

brain-derived neurotrophic factor - BDNF) to these neurons their degeneration and death can be prevented.

We are developing new technology that will enable us to deliver BDNF in a safe and effective manner that provides long-term neural protection. Using nanoengineering techniques, we have developed particles that can load and release therapeutic levels of BDNF to protect the auditory neurons. Using a deafness model, we have shown that treatment with BDNF-loaded particles was effective in preventing the degeneration and death of the auditory neurons.


— Developed a drug delivery system based on nanoengineering

— Shown we can load and release effective amounts of therapeutics

— Obtained preliminary in vivo data indicating that drug-loaded particles can protect the auditory neurons from degeneration and death.

This study has provided important pre-clinical data indicating that the particle technology is a safe and effective drug delivery technique that has the potential to be used clinically.

Research Team: Dr Andrew Wise, Prof Rob Shepherd, and Dr Justin Tan.

External collaborators: Prof Frank Caruso and Dr Yajun Wang (University of Melbourne).

Funding: NHMRC.

Image of a sensory cell (red) and the auditory neurons (green) that make connections to the cell in order to convey sound information to the brain. The sensory cells are easily damaged, which in turn leads to the degeneration and death of the auditory neurons.

(a) An inner hair cell (IHC; white cell) protected from degeneration after noise-induced hearing loss by brain-derived neurotrophic factor gene therapy (green cells). The sensory region of the cochlea is circled with hair cells labelled white, supporting cells labelled blue and neurons labelled red. (b) Atoh1 gene therapy (green cells) transformed residual supporting cells into hair cells (HC; white cells) in an otherwise severely damaged sensory region of the cochlea in which all other cells have been lost due to noise exposure. The sensory region of the cochlea is circled with cell nuclei labelled in blue.


Bionic Hearing

Research Team: Dr Elisha King, Prof Rob Shepherd, and Dr James Fallon.

External collaborators: Prof Alec Salt (University of Washington); Prof Ian Curthoys and Dr Daniel Brown (University of Sydney); and Prof Stephen O’Leary (University of Melbourne).

Funding: Garnett Passe & Rodney Williams Memorial Fund.

Improving music sound quality with cochlear implantsCochlear implants (CIs) have been designed primarily to convey speech information. Complex signals such as music contain broader frequency (spectral) content than speech – perception of pitch and timbre both require fine spectral detail in the signal. Unfortunately, spectral detail is degraded by the sound processor, reducing much of the appeal of music. However, music has an undeniable cultural and social importance, and the lack of music appreciation negatively affects quality of life. Considering the pervasiveness of music, we are addressing this problem in order to

Optimising drug delivery to the oval window to improve the treatment for Ménière’s disease Symptoms of Ménière’s disease (MD) include rotational dizziness (vertigo), temporary hearing loss, and ringing in the ears (tinnitus). The most common clinical treatment is an injection of antibiotic gentamicin through the ear drum. Gentamicin is toxic to the sensory cells in both the vestibule (organ used for balance) and the cochlea (organ used for hearing). A single local injection can decrease the incidence of vertigo in MD by ablating the sensory cells in the vestibule. However the side-effect of permanent hearing loss can occur in some patients. Another significant problem with the current treatment is variable therapeutic outcomes for patients due to the variability of drug levels entering the inner ear. The aim of this research is to address these issues by investigating better ways to deliver gentamicin to the inner ear.

In our previous research (conducted at the Department of Otolaryngology, University of Melbourne), we found that drugs enter the inner ear in large quantities in a location which has been largely ignored until recently. We found that substances can enter the vestibule directly in the vicinity of the stapes footplate (base of a small bone in the middle ear) when a small volume of highly concentrated gentamicin was applied to it in an animal model. Hearing was tested before and after the treatment and compared to groups receiving gentamicin on a location near the cochlea or saline controls. There was greater hearing loss and sensory cell loss following gentamicin delivery on the stapes footplate than any other group.

The conclusion that gentamicin enters the vestibule directly in the vicinity of the stapes footplate has significant ramifications for MD treatment.

We have recently commenced a project investigating whether targeting a small volume of optimised gentamicin dosage can improve the control of drug levels in the inner ear and reduce the potential side effects (such as permanent hearing loss) associated this current treatment for Meniere’s disease.

improve the wellbeing and the productivity of people with impaired hearing.

Our research aims to improve the perception of music in cochlear implant recipients by better understanding the factors that will affect the perception of pitch.

Using a cochlear implant, the sensation of pitch is mainly induced by the position of the electrode activated and the region of auditory nerves stimulated. However the spread of electrical current increases with the intensity of the signal, leading to a possible difference in pitch perception. Our experiments have shown that timbre and intensity levels of sound can change the perception of pitch for CI users. In bimodal listeners (i.e., those with a CI in one ear and a hearing aid in the other) this potentially leads to pitch mismatches between the two ears as intensity and timbre vary (see next project description for details).

In collaboration with the University of Melbourne, we are developing a new auditory training method based on multimodal reinforcement through a custom-made metallophone. This instrument provides a direct spatial representation between pitch height and position (visual congruence) and requires the recipient

Hearing threshold shifts at five stimulus frequencies measured 1 week following gentamicin or saline administration on the stapes footplate or round window membrane (RWM). Bars indicate standard error of the mean. Statistically significant threshold elevations indicated by asterixes (*) were observed following gentamicin administration to the stapes footplate at 8, 16, 24 and 32kHz, compared to RWM and to both saline control cohorts. The larger hearing loss when gentamicin was applied to the stapes footplate suggests more gentamicin entered the inner ear in that condition.

Sensory cell counts in three regions in the vestibule (organ used for balance). Cell counts were compared for gentamicin or saline applications to the stapes or round window membrane (RWM). In all groups, sensory cell counts were normalised with respect to those of the untreated, opposite ear. Error bars indicate standard error of the mean and asterixes (*) indicate a significantly different percentage.


The change in the number of stimulated neurons as stimulation level increases (current spreading). When stimulation level increases on one single electrode, more neurons are stimulated. The effect of current spreading on the perceived pitch depends on the number and place of stimulated neurons. The place pitch percept may become higher or lower depending on whether the current spreading is greater in the basal or apical direction.

The mean change in the matched frequency in semitones for different participants at low and high frequencies. This graph illustrates the large variability of the perceived pitch with increases in the intensity of the reference sounds.

Specifically designed harmonic metallophone that will be used to train cochlear implant users to better perceive music.

to produce a motor movement related to pitch height. We are currently developing exercises with the instruments designed to improve pitch discrimination ability as well as auditory working memory. We are hoping that this training will help cochlear implant users to better perceive music and understand speech in noise.


— Obtained a better understanding of the effect of loudness on the perception of musical pitch

— Studied the interaction between vowels and pitch

— Developed a new musical training program.

Research Team: Dr Jeremy Marozeau, Dr Hamish Innes-Brown, Mr Mohammad Maarefvand, Mr Jason Gavrilis and Ms Ninia Simon.

External collaborators: Prof Sarah Wilson, A/Prof Neil McLachlan, and Ms Jo Wigley (University of Melbourne).

Funding: NHMRC; Victorian Lions Foundation.

Improving music perception in bimodal cochlear implant usersPitch perception is usually poor in cochlear implant (CI) users, and some studies have shown that aspects of sounds like intensity and timbre can influence pitch perception. Recent studies have shown that the effect of intensity on the perception of pitch is greater than expected. In addition to this, differences in pitch perception between hearing aids and cochlear implants make the perception of pitch more complicated for people using bimodal hearing. It potentially can lead to a pitch mismatch between the two ears and this is particularly important in the perception of musical sounds.

This study aimed to investigate the perception of pitch for sounds with different timbre and intensity in bimodal listeners. The factors we identified will need to be taken into account in efforts to improve music perception for CI users. This is particularly important because changes in intensity and type of sounds are more common in music than in speech.

In the past year we have found:

— The frequencies of matched sounds were different for different types of reference sounds, and this effect was highly significant

— Changes in intensity changed the matched frequency for some users by up to ten semitones

— A large inter-subject variability was observed for all types of sounds and the change in matched frequency between soft and loud sounds depended on the type of reference sound.

Research Team: Mr Mohammad Maarefvand (PhD student), Prof Peter Blamey, and Dr Jeremy Marozeau.

External collaborators: Dr Julia Sarant (University of Melbourne).

Funding: Iranian Health and Medical Sciences Ministry PhD scholarship to Mr Mohammad Marrefvand.

Improving auditory stream segregationAuditory streaming is the ability to segregate and combine different auditory information streams and is mainly based on perceptual differences between sound sources. Unfortunately, the cochlear implant (CI) degrades the acoustic cues that give rise to perceptual differences between sound sources, thus reducing the ability of the CI user to segregate different sound sources.

Our previous research suggested that musical streams are easier to segregate when the difference in pitch between the two streams is large. In the present study we used short piano pieces known to evoke happy or sad emotional responses in normally-hearing (NH) listeners. We increased the perceptual distance between streams by sending the two parts of the pieces to different ears in 11 normally-hearing adult participants, or different hearing devices for 11 bimodal listeners (a CI in one ear and hearing aid in the other ear) and eight bilateral CI listeners. We recorded three ratings after each short


Bionic Hearingpiece was played: a happy/sad emotional rating, a like/dislike aesthetic rating and a clear/unclear stream segregation rating. We hypothesised that the emotional, aesthetic and stream segregation ratings would improve when the two parts were sent to separate ears compared to when they were combined in a single ear.

On average, hearing-impaired participants successfully rated the happy pieces as happy and the sad pieces as sad. Cochlear implant users were thus able to discern the emotional content of simple piano pieces without additional separation of the melody and harmony. However, separating the parts did significantly improve stream segregation ratings for both hearing-impaired groups. We also found that hearing-impaired listeners preferred listening to happy pieces compared to sad pieces, while normally-hearing listeners made equal aesthetic ratings for happy and sad pieces. Further acoustic analysis of the differences between happy and sad pieces may help to explain this unexpected effect.


— Tested a new method that facilitates the segregation of auditory streams by enhancing the perceptual differences between the sound sources

— Shown that this method helped cochlear implant recipients to accurately judge the emotional content of music.

— Shown that this method had a positive impact on cochlear implant recipients’ appreciation of the music.

Research Team: Dr Jeremy Marozeau and Dr Hamish Innes-Brown.

External collaborators: Prof Isabelle Peretz (University of Montreal).

Funding: NHMRC.

Using novel cochlear implants with focused all-polar stimulation to improve perceptionDespite having good speech understanding in quiet environments, cochlear implant recipients experience difficulties in noisy situations. Studies have suggested that such difficulties are partly due to the broad spread of current from each electrode,

so that different frequencies in speech are not separately heard. To reduce this spread, a new stimulation strategy (termed all-polar) is being investigated. The strategy uses multiple simultaneous currents to focus the current into highly specific regions in the cochlea. A research implant that uses this strategy is presently being used by five volunteers. The research implant can use 22 simultaneous current sources via a bench-top stimulator and percutaneous connector.

To date, four experiments have been performed that compared the conventional (monopolar) mode of stimulation (which uses a single intra-cochlear electrode) and the new strategy.

Experiments 1 and 2 tested whether the all-polar mode leads to more independence of timing (temporal) information between the intra-cochlear channels. These experiments did not show a difference between the two modes.

Experiment 3 tested the hypothesis that that there may be a neural mechanism that detects synchronies across different cochlear places. Such a mechanism has been proposed as important for pitch perception in normal hearing. Our results showed that patients were able to tell the difference between the synchronous and non-synchronous stimuli using both monopolar and all-polar stimuli, supporting the hypothesis that there is a neural mechanism for detecting synchrony across cochlear place, and leading to potential ways to improve pitch perception for cochlear implant users.

Experiment 4 investigated whether the all-polar strategy can improve the ability to distinguish between different vowel sounds. Stimuli were created to represent two spectral peaks associated with four different vowels using sequential and simultaneous monopolar and all-polar modes. After a training period, patients were asked to identify each stimulus with its corresponding vowel. Results showed that accuracy scores were greater for both all-polar modes compared to the monopolar modes. We can conclude that an all-polar stimulation strategy may allow better discrimination of vowels.


— Continued to test the new stimulation strategy in five patients

Identification of “happy songs” as happy and “sad songs” as sad by CI recipients.

When presented with the enhanced segregation cues, CI recipients judged stimuli as clearer than when presented with the standard sound processing strategy.


In monopolar mode the current flows between a single electrode to an extracochlear return electrode. In bipolar mode the current flows between two nearby electrodes. In the all-polar mode many electrodes will be activated to create a focussed electrical field.

All-polar stimulation mode yields a higher vowel recognition score.

— Found that early results suggest that the new strategy can improve the distinction between different vowel sounds and therefore may improve speech perception.

Research Team: Prof Colette McKay, Dr Jeremy Marozeau, and Prof Hugh McDermott.

External collaborators: Dr Brett Swanson (Cochlear CRC) and Prof Robert Briggs (Hearing CRC).

Funding: Garnett Passe & Rodney Williams Memorial Foundation and Cochlear Ltd.


As part of the Bionic Vision Australia consortium the Bionics Institute designed, manufactured and rigorously tested Australia’s first prototype bionic eye. In 2012, this device was successfully implanted in three patients with retinitis pigmentosa, the most common cause of inherited blindness. In a world-first this device was implanted between the two back layers of the eye (suprachoroidal location) and has proven to be both safe and effective.

Bionic Vision

BVA is a national consortium of researchers from the Bionics Institute, the Centre for Eye Research Australia (CERA), NICTA, the University of Melbourne and the University of New South Wales. The Royal Victorian Eye and Ear Hospital, the National Vision Research Institute and the University of Western Sydney are project partners. BVA is funded through a Special Research Initiative “Research in Bionic Vision Science and Technology” grant from the Australian Research Council.

The Bionics Institute is responsible for the preclinical program and also plays a key role in psychophysics testing and vision processing design. The Institute’s bionic vision research is also funded by The Bertalli Family Foundation.

During the past year we have:

— Characterised the visual perceptions evoked by the prototype device

— Shown that patterns recognisable as letters and numbers can be produced by stimulating multiple electrodes

— Worked on the vision processing strategies that will transform the visual world captured by a camera into patterns of electrical stimulation across the electrode array

— Examined ways to increase the number of electrodes in the array

— Conducted safety studies on positioning and securing a prototype high-acuity bionic eye (made from conductive diamond) on the retina’s surface.

PROJECTS:

The next generation of bionic eye devicesBionic Vision Australia (BVA) is developing two devices for vision-impaired patients: a wide-view device with 98 electrodes to provide patients with the ability to navigate their environment; and a high-acuity device with many more electrodes to provide more detailed, central vision.

The Wide-View Retinal Implant

Preclinical studies were used to further our knowledge about electrical stimulation of the retina with the wide-view electrode array located in the suprachoroidal space. Degenerate retinae in our preclinical model were shown to be activated with similar parameters as normal retinae. This suggests that the electrical stimulation in both cases activates the deepest neural layer in the retina, bypassing the outer sensory (light-receptive) cell layer and the pre-processing neural layer. It has been proposed that electrical stimulation from the outer surface of the retina would result in outer layer stimulation; however, these initial results suggest that the deepest retinal (ganglion cell) layer is being activated directly with suprachoroidal stimulation. This is important because it indicates that we are stimulating the desired targets (the ganglion cells that give rise to the optic nerve) as opposed to

the light receptive cells that are destroyed in retinal diseases.

Further analysis of these stimulation experiments will be carried out to differentiate the responses of the retinal ganglion cells and cells within the light-receptive and pre-processing cell layers.

The effect of specific electrical stimulus parameters on retinal stimulation has been explored further in the past year. We have characterised the effects of duration of the bi-phasic stimulation pulses, rate of stimulation, inter-phase gap, among others. The preclinical models have allowed us to explore a wider range of parameters than is possible with human participants due to the direct and precise quantification of neural responses and faster turn-around of stimulation protocols.

After the initial pilot clinical trial with the prototype bionic eye, a primary goal is to extend the visual field and increase the electrode count in the prosthesis to provide more detailed and useful perception. In collaboration with the University of New South Wales, we have evaluated a novel micro-fabrication technology based on laser patterning of platinum and silicone. Electrode arrays made with this thin-film technology were evaluated with acute and chronic implantation in an animal model to evaluate the safety and efficacy of this technology. In parallel, we have extended the micro-moulding and wire routing fabrication technologies within the Bionics Institute to explore the limits in electrode


count for a wide-view retinal prosthesis. A flexible helical lead, for connecting to the suprachoroidal implant, with increased number of wires (more than double) has shown promise in initial durability testing. Further evaluation of advanced micro-fabrication technologies will continue, with the aim to produce a second generation wide-view retinal prosthesis for the clinic.

In the past year:

— The wide-view implant was used to stimulate degenerate retina in a blind preclinical model

— New technologies were evaluated to increase the number of electrodes beyond the 24 channels in the first prototype

— The parameters of electrical stimulation for activating the retina were explored further, and reliably predicted the results observed with the first implanted patients.

The 24 channel suprachoroidal prototype bionic eye.

The High-Acuity Retinal Implant

The BVA’s high-acuity program is focusing on the development of a conductive diamond device that is positioned on the surface of the retina (epiretinal location).

Experiments have been progressing over the past 12 months looking at the safety and efficacy of positioning and securing this device with different methods. Integral to the development of these methods, we have found that the shape or ‘form factor’ is of crucial importance for the long term stability of the implant.

We have been assessing the use of retinal tacks as a safe and effective attachment method to the retina. The aim was to determine whether the tack would hold the device in place while causing minimal damage to the retina. In a series of iterative studies the silicone body of the implant, the cable system and the tack dimensions were developed to obtain optimal device

placement and minimal retinal damage. While retinal tacks have been featured in other retinal prostheses internationally, our studies found they were a less than perfect solution for situating a prosthesis on the retina. We have begun investigating alternate methods for securing the diamond array on the retina, with the aim of developing a fixation technique that will position the diamond electrode array close to the retinal ganglion cells (give rise to the optic nerve) without compromising the structure of the retina.


— Found that achieving reliable fixation of a retinal prosthesis to the retina is a delicate combination of fixation method, ‘form’ of the retinal prosthesis and cable design

— Continued to work on optimising the methods for prosthesis fixation

Prototype high-acuity device showing the twenty-five conductive diamond electrodes in the centre of the device. The conductive diamond electrode is manufactured by collaborators at the University of Melbourne (Physics) while the chip driving the device has been designed by NICTA.

Schematic showing two possible locations of an electrode array (suprachoroidal or epiretinal).

— Continued to refine surgical procedures alongside device development.

Placement of Next Generation Wide-View Device and the Prototype High-Acuity Device

The main aim of the high-acuity device study was to investigate the effects of a passive device implanted in the epiretinal space. The study illustrated the need for a more stable retinal fixation method within the eye. The vitrectomy surgery time has reduced significantly over the past year. Use of flexible glue during surgery was also established. There are many challenges associated with fixing a retinal prosthesis in the epiretinal space due to the delicate nature of the retina. Once the fixation method is established it will offer the advantage of stimulating the retinal ganglion layer at a closer proximity than other sites of implantation.

In the past year:

— The vitrectomy surgery required for implantation of the high-acuity device was developed.

— High-acuity array fixation to the retina was developed and evaluated.

Research Team: A/Prof Chris Williams, Dr David Nayagam, Dr Mohit Shivdasani, Dr James Fallon, Dr Jin Xu, Dr Joel Villalobos, Ms Rosemary Cicione, Dr Sam John, Mr Ronald Leung, Ms Alexia Saunders, Ms Michelle McPhedran, Mr Rodney Millard, Mr Mark Harrison, Mr Owen Burns, Ms Ceara McGowan, Mr Felix Aplin, Ms Lisa Cardamone, Ms Vanessa Maxim, Ms Helen Feng, Prof Peter Seligman, and Prof Rob Shepherd.


Bionic VisionExternal collaborators: Dr Penny Allen, Dr Mark McCombe, and Dr Jonathan Yeoh (Royal Victorian Eye and Ear Hospital); Dr Chi Luu, Dr Lauren Ayton, Dr Carla Abbott, and Mr Nick Opie (Centre for Eye Research Australia); A/Prof Richard Williams (Department of Pathology, University of Melbourne); A/Prof Penny McKelvie and Ms Meri Basa (St Vincent’s Hospital Melbourne); Dr Hamish Meffin (NICTA); Mr Chris Dodds, and A/Prof Gregg Suaning (University of NSW); Prof John Morley (University of Western Sydney); Dr Kumar Ganesan, Dr David Garret, Dr Kate Fox, Dr Arman Ahnood and Prof Steven Prawer (Melbourne Materials Institute); Prof Michael Ibbotson and Dr Shaun Cloherty (National Vision Research Institute); and Prof Anthony Burkitt and Ms Tamara Brawn (Bionic Vision Australia).

The safety of replacing a suprachoroidal retinal prosthesisRetinitis pigmentosa is an inherited condition that causes severe degeneration of the outer retina. The recent clinical trial has shown that electrode arrays implanted adjacent to the retina in a suprachoroidal location can restore visual percepts to patients who are blinded by retinitis pigmentosa. The ability for these arrays to be replaced is an important aspect of implant safety. For example, replacement may be necessary if the device malfunctions or an improved device becomes available. We therefore investigated whether a suprachoroidal retinal implant could be safely replaced and determined the effect of the procedure on the eye.

We demonstrated that these devices could be surgically replaced with minimal intra-operative or post-operative complications. There were no clinical or histologically signs of damage to the retina or surrounding tissues after device replacement. Furthermore, the electrophysiological response of the retina was not different to eyes with non-replaced electrode arrays.

These results indicate that recipients of suprachoroidal retinal prostheses will not be precluded from receiving an improved device in the future.


— Suprachoroidal retinal prostheses can be replaced using simple surgical techniques

— Device replacement can be performed safely with minimal damage to surrounding tissues

— Retinal function is preserved even after device replacement.

Research Team: Mr Ronald Leung (PhD student), Dr David Nayagam, Dr Mohit Shivdasani, Prof Rob Shepherd, A/Prof Chris Williams, Ms Alexia Saunders, Ms Helen Feng, Mr Owen Burns, Dr Joel Villalobos, Ms Michelle McPhedran, Ms Ceara McGowan, Ms Rosemary Cicione, Dr Sam John and Mr Felix Aplin.

External collaborators: Dr Elizabeth Bowman, Dr Penelope Allen, Dr Chi Luu, Dr Jonathan Yeoh, Dr Lauren Ayton (Centre For Eye Research Australia); A/Prof Richard Williams, Dr Cesar Salinas-La Rosa and Dr Meri Basa (St. Vincent’s Hospital Melbourne).

Funding: Australian Postgraduate Award to Mr Ronald Leung.

Spatiotemporal interactions in the visual cortex using paired electrical stimulation of the retinaTo enable patterned bionic vision, for example of shapes, electrical stimulation of multiple electrodes on a retinal prosthesis is required. However, discordant interactions may occur with multi-electrode stimulation. This project is investigating the interactions that take place with stimulation of a pair of electrodes on a suprachoroidal prosthesis and the effect of distance, time and current on the resultant neural interactions in the visual cortex. Interactions were quantified by comparing action potential (spike) counts following paired stimulation with that evoked by stimulation of a single electrode.

The retina was stimulated using a paired-pulse paradigm where the current of the first pulse (0-1.5mA) and the delay between the two pulses (1.025ms-500ms) were varied. The current of the second pulse was kept constant. Pulses were presented on electrodes separated by 0, 1 or 2mm. Spatiotemporal interactions were found to extend over several millimetres of the retina and resulted in a reduction in cortical spiking activity after the second pulse when both pulses were present compared to when only the second pulse was present. These interactions were dependent on the amplitude of the first pulse and the delay between the two pulses. For delays beyond 100ms, there was no significant interaction between the stimuli, irrespective of the amplitude of the first pulse.

The retina overlying the bionic eye remains healthy after the device is replaced.

The anatomical structure of the eye overlying the electrode array (indicated by arrows) is preserved after device replacement.


The paired-pulse electrical stimulation paradigm. Two electrodes were chosen to determine how electrical stimulation of the first electrode (P1, red) affects spiking activity evoked by electrical stimulation of the second electrode (P2, blue).

Changes to spiking activity after P2 evoked by paired stimulation. (Top) Example of spikes recorded in the visual cortex when only the second electrode is electrically stimulated. (Bottom) Example of spikes recorded in the visual cortex during paired-pulse stimulation. The presence of P1 resulted in a reduction in spikes evoked by P2.

Knowledge of the neural interactions evoked when using multi-electrode stimulation is essential for developing effective patterns of electrical stimulation for retinal prostheses. Results of such interactions should be carefully taken into account when developing complex spatiotemporal patterns of stimulation.

In the past year we found:

— Interactions between electrical stimulation of two retinal electrodes in a suprachoroidal array resulted in a reduction of neural spiking activity recorded in the visual cortex

— Interactions varied as a function of both current and time between pulses

— Interactions can exist between two stimuli presented on the same retinal electrode as well as two electrodes separated by as much as 2mm.

Research Team: Ms Rosemary Cicione (PhD student), Dr Mohit Shivdasani, Dr James Fallon, Mr Graeme Rathbone and A/Prof Chris Williams.

Funding: Latrobe University Postgraduate Research Scholarship to Ms Rosemary Cicione.

Optimising electrical stimulation for suprachoroidal retinal prosthesesRetinal prostheses are a promising treatment for people suffering from retinal degenerations. Currently there are few guidelines that aid in selecting the most effective stimulus parameters. This project aimed to provide insight into the fundamental effects of stimulation parameters such as impedance, polarity,

duration, interphase gap and pulse rate on cortical neural responses. The results provided important feedback into designing safe and effective stimulation paradigms for retinal prostheses. They also provided further understanding of how the brain decodes electrical stimulation.

We cautiously advance in this work as patient safety is of utmost importance. Retinal prostheses require higher charge to activate retinal cells (compared to other neural prostheses) and pose a challenge as the effects of chronic stimulation with retinal prostheses are largely unknown. Long-term safety studies ranging from weeks to months are required to establish safety limits for retinal stimulation. Further research is also required to understand how the brain adapts in long-term visual deprivation and the plastic changes from prolonged electrical stimulation of the retina.

In the past year we found:

— 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

— Based on our results, anodal first biphasic pulses between 300 - 1200 µs are recommended for suprachoroidal retinal stimulation.

Research Team: Dr Sam John (PhD student), Dr Mohit Shivdasani, A/Prof Chris Williams, Prof Rob Shepherd, Mr Graeme Rathbone and Dr James Fallon.

External collaborators: Prof John Morley (University of Western Sydney); Dr Chi Luu (Centre for Eye Research Australia).

Funding: La Trobe University Postgraduate Research Scholarship and La Trobe University Full Fee Remission Scholarship to Dr Sam John.

Psychophysics and vision processingThe visual psychophysics studies aim to characterise how visual percepts produced by bionic eye devices can be controlled by varying stimulation parameters. The results obtained divulge the vision processing strategies that should be used to provide real-world visual information to the user.

Psychophysics

Over the last year, weekly psychophysics sessions have been undertaken with three patients implanted with the prototype 24 channel suprachoroidal retinal prosthesis. Visual percepts, known as phosphenes, have been successfully elicited in all three patients, with quite different stimulation parameters proving optimal in each case.


Bionic Vision

Individual electrodes were found to produce phosphenes in defined areas of the visual field, with their shape and size varying as a function of electrode position. Phosphene shapes ranged from simple ovals or blobs, to quite complex forms with light and dark components. Electrode identification tasks performed with two patients have shown that individual phosphenes are distinguishable and identifiable. Patterns recognisable as letters and numbers have also been produced for two patients by stimulating multiple electrodes.

The psychophysics testing is ongoing, with work planned for further investigating multiple electrode stimulation and for exploring the dynamic properties of visual percepts. Future testing is also planned for two other bionic eye devices, as part of the BVA program.

In the past year:

— Visual percepts have been successfully elicited in all three patients implanted with a suprachoroidal electrode array

— Visual percepts have been characterised (including shape, size and location in the visual field) for a range of stimulation parameters

— Patterns recognisable as letters and numbers have been produced for two patients by stimulating multiple electrodes.

Research Team: Prof Peter Blamey, Prof Hugh McDermott, Mr Nicholas Sinclair, Dr Mohit Shivdasani, Dr Matt Petoe, Dr Lisa Gillespie, Dr Thushara Perera, Mr Kyle Slater, and Prof Peter Seligman.

External collaborators: Bionic Vision Australia, including: Dr Peter Dimitrov, Ms Mary Varsamidis, Dr Lauren Ayton and Dr Chi Luu (CERA).

Effect of pulse duration: threshold versus pulse duration. (a) Shows the mean current threshold for monophasic pulses; (b) shows the corresponding mean charge threshold for monophasic pulses; (c) shows the mean current threshold for biphasic pulses; and (d) shows the corresponding mean charge threshold for biphasic pulses. The x-axis shows the pulse duration. The dashed lines indicate the four regions of activation based on the chronaxie-c. R1= [D ≤ 0.25 x C], R2= [0.25 x C < D ≤ 0.5 x C], R3= [0.5 x C < D ≤ C], and R4= [D > C]. Error bars show the standard error of the mean (n= 140).

v: Histogram of the k-values calculated using the empirical model described by Shannon (1992) in each region R1-R4. Dotted line represents the most conservative boundary for non-damaging stimulation of k =1.7.

Vision Processing

Vision processing continues on from the work of the visual psychophysics team by using the information on the size, brightness, and position of the visual percepts to construct artificial vision for the implantees. The video camera was ‘switched-on’ for the three patients in early 2013, and immediately each patient was able to locate a bright light in a darkened room. Subsequent refinement of the vision processing strategies, in collaboration with NICTA, has enabled the patients to describe the location and shape of objects on a computer screen and pass standard low vision clinical tests. By comparing the repeat performance of the patients in these tests, we have been able to select strategies that significantly enhance the implant’s operation. For example, we have found that performance on a pattern recognition task is improved by the use of higher electrode stimulation rates.

Future tests that will be conducted using the vision processing system will examine patient performance on mobility, navigation, and tasks of hand-and-eye co-ordination.


Suprachoroidal retinal prosthesis recipient Dianne Ashworth tracing a visual percept with her index finger. A motion tracker is used to record finger position and capture the drawing (overlaid in red).

Electrode identification results for two patients of the suprachoroidal study. Individual electrodes were stimulated in a random order and the patient was asked to estimate which electrode was used. The plot shows histograms of the distance between the estimated and actual electrodes, with 0mm corresponding to the electrode being correctly identified. The results show that the patients correctly identify the actual electrode (0mm) or a neighbouring electrode (1mm) in the majority of trials (95% of trials for Patient 1 and 76% for Patient 2).

Vision processing for the bionic eye involves selecting a portion of a video image that corresponds to the implant field-of-view (shown in A by a red box). This image portion is analysed (B) and a decision made on which electrodes should be turned on (C). The signal sent to the implant tells which electrodes should be turned on and at what strength (D).

Suprachoroidal retinal prosthesis recipient Dianne Ashworth tracing a letter ‘C’ on a computer screen with her index finger. The image from the video camera mounted on her forehead is processed by a computer and sent to the implanted electrodes.

In the past year:

— All three bionic eye patients have been fitted with a vision processing system that transmits video images to their electrode array

— Patients are able to locate objects in a room and describe the location and size of objects on a computer screen

— Work has progressed on letter recognition and mobility studies.

Research Team: Prof Peter Blamey, Prof Hugh McDermott, Dr Matt Petoe, Mr Nicholas Sinclair, and Dr Mohit Shivdasani.

External collaborators: Bionic Vision Australia, including: Dr Chris McCarthy and A/Prof Nick Barnes (NICTA); Dr Peter Dimitrov, Ms Mary Varsamidis, Dr Lauren Ayton and Dr Chi Luu (CERA).


The Bionics Institute is developing neurobionic (brain stimulation) technologies that offer a new approach for a range of debilitating neurological and psychiatric disorders that are otherwise unresponsive to current therapies. These technologies are an evolutionary step from our development of the bionic ear and, more recently, the bionic eye.

Our goal is to bring these devices to the clinic as soon as possible so that the millions of people with epilepsy, chronic pain, Parkinson’s disease, obsessive compulsive disorder, and other conditions will benefit within the next decade.

During the past year we have:

— Expanded our neurobionics team with the aim of trialling a number of devices for a range of disorders in the next five years

— Continued to develop a device for monitoring and controlling epileptic seizures

— Continued to develop an innovative deep brain stimulation (DBS) device with advantages over existing technologies such as smaller electrodes for more precise stimulation of the brain and fewer side-effects

— Undertaken clinical studies with essential tremor patients to improve outcomes with existing DBS devices

— Commenced a postural stability study in Parkinson’s disease patients with an existing DBS device that is examining the relationship between different patterns of brain stimulation and patients’ ability to maintain balance

— Partnered with clinicians and other researchers to commence a study of DBS in patients with intractable obsessive-compulsive disorder

Neurobionics

— Developed a new clinical grade peripheral nerve stimulation platform for the treatment of chronic neuropathic pain.

PROJECTS:

An innovative device for diagnosis and treatment of epilepsyEpilepsy is a chronic disorder of the brain that results in recurrent and unpredictable seizures. Three to four percent of the Australian population will develop epilepsy during their lifetime. It can develop at any age, regardless of gender or ethnic group, and up to one third of epilepsy patients cannot gain control of the condition through medication or other means. The unpredictable nature of seizures can force people to become house-bound, and thus lead to a withdrawal from everyday activities and a reduction in quality of life. In extreme cases, surgery is performed to remove the region of the brain suspected to be the cause of the seizures. This surgery is highly invasive, non-reversible, and carries no guarantees of success. There have been several studies where people with difficult-to-control epilepsy have had fewer seizures after having surgery to implant an electrical stimulation device. The Bionics Institute is developing neurobionic technologies that offer a new approach for monitoring

and controlling epileptic seizures, ideally returning to patients the freedom and safety that most of us take for granted. The neuroBi is a prototype device optimised for these studies.

While epileptic seizure occurrence often appears random, there is evidence that the brain undergoes subtle but detectable changes prior to seizures and during seizure onset. This project aims to develop a device for treating epilepsy that enables anticipation, detection, and suppression of an impending seizure. A detection algorithm has been developed, tested, and proven safe and effective in animal models. Current work is aimed at obtaining evidence of efficacy in patients. The neuroBi device has been approved for clinical trials in patients prior to surgical treatment of their epilepsy. Seizure anticipation, detection, and stimulation functions will be assessed. Participants are currently being recruited for this trial.

In the past year:

— Approval has been obtained from the St Vincent’s Hospital ethics committee to conduct a trial of neuroBi, an innovative device designed by the Bionics Institute, with adults receiving treatment for epilepsy

— Four neuroBi units have been assembled and tested in preparation for the initial clinical trial.


The neuroBi is a prototype device developed at the Institute for monitoring and controlling epileptic seizures.

Research Team: Prof Hugh McDermott, Prof Peter Blamey, A/Prof Chris Williams, Mr Graeme Rathbone, Mr Rodney Millard, Mr Mark Harrison and Mr Kyle Slater.

External collaborators: Prof Mark Cook (St Vincent’s Hospital Melbourne and the University of Melbourne); Prof Anthony Burkitt, A/Prof David Grayden, Dr Alan Lai and Dr Dean Freestone (University of Melbourne); and A/Prof Wendyl D’Souza and Mr Simon Vorgrin (St Vincent’s Hospital Melbourne).

Funding: NHMRC, ARC, St Vincent’s Research Endowment Fund.

Results for the fitting of intracranial EEG recordings from the hippocampus of an in vivo model of temporal lobe epilepsy to a neural mass model.

The top graph shows the original EEG recordings used for the estimation procedure. For this recording the seizure onset occurs at 0s and terminates at the dotted line. The next three graphs show the estimated synaptic gains for the excitatory (Gp), slow inhibitory (Gsi), and fast inhibitory (Gfi), populations. The bottom graph shows the estimated input mean to the model cortical region.

Recorded and simulated seizure activity. (A) Intracranial EEG recorded from the hippocampus of an in vivo model of temporal lobe epilepsy. (B) Artificial EEG generated using a neural mass model of the hippocampus. The dotted red lines in (A) and (B) correspond to the times at which the recorded seizure begins and ends.

A novel integrated circuit towards improved treatment and diagnosis of epilepsyEpilepsy is the most common serious neurological disorder, affecting more than 1% of the world’s population. Of these people, approximately 30% suffer from uncontrollable seizures despite modern drug therapies. Promising new research has demonstrated that electrical stimulation can prevent the manifestation of epileptic seizures. To this end, we are developing a fully implantable seizure abatement system. A critical and large part of this work involves designing and fabricating a chip that will expand the capabilities of approved implantable stimulators (such as the cochlear implant). This chip will enable the development of an implantable system that can be used to chronically monitor and stimulate the brain.

Over the past year we have refined the architecture of our custom chip, ‘XPAND’. With this finalised we are now working towards fabricating the chip, and plan to do so in early 2014. This first version will expand the existing cochlear implant from 24 to 64 electrodes. It will also enable more flexibility in how we can connect to these electrodes, enabling flexible recording and stimulation capabilities. This system will form the basis of a new generation of implantable devices that has the potential to improve the diagnosis and treatment of epilepsy.


— Finalised the ‘XPAND’ integrated circuit architecture

— Developed novel circuitry providing a biologically safe power and communication interface

— On track to fabricate ‘XPAND’ in 2014.

Research Team: Mr Kyle Slater (PhD student) and Prof Hugh McDermott.

External collaborators: Dr Simone Gambini, A/Prof David Grayden and Prof Stan Skafidas (University of Melbourne); Prof Mark Cook (St Vincent’s Hospital Melbourne and the University of Melbourne).

Funding: The Colonial Foundation, The Pierce Armstrong Foundation, The Eirene Lucus Foundation, and an Australian Postgraduate Award to Mr Kyle Slater.

Tracking physiological changes that lead to seizure: A computational model-based approachEpilepsy can result from numerous and different neural pathologies which often contributes to difficulties in treatment. This project aims to determine how the underlying physiology of the brain alters as a seizure is approaching, and to make use of electrographic data to determine effective patient-specific treatments.


Using a computational model of a small cortical region, this project is investigating the mechanisms involved in seizure generation. Using the results, the aim is to investigate whether differences in the mechanisms involved in seizure generation can be used as a predictor of the efficacy of different treatments including electrical stimulation and drugs.

Our experiments have shown that changes in the synaptic strengths of both excitatory and inhibitory neural populations result in the transition to seizure. Using a model-based approach allows us to estimate the physiological aspects of the brain that are normally unobservable. The results of this study suggest that the mechanism involved in seizure generation and termination vary between individuals. This suggests that patient-specific modelling is required in order to improve the treatment of epilepsy.

A future aim is to investigate the effect of therapy on estimated physiology, and whether the results are linked to the different mechanisms involved in seizure generation.


— A statistical inference method can be used to estimate physiological aspects of seizure generation and termination in an in vivo model of epilepsy

— The mechanisms involved in seizure generation vary between individuals with the same type of epilepsy

— Mean neural firing rates of cortical regions can be estimated using a model-based approach.

Research Team: Mr Richard Balson (PhD student) and Prof Peter Blamey.

External collaborators: Prof Anthony Burkitt, A/Prof David Grayden, and Dr Dean Freestone; Prof Mark Cook (St Vincent’s Hospital Melbourne and the University of Melbourne).

Deep brain stimulation studies and device development Deep brain stimulation (DBS) is emerging as a safe and effective treatment for people with a range of serious disorders that do

Neurobionics

not respond adequately to established therapies. It is a surgical procedure that uses an implanted medical device to deliver controlled electrical stimulation to targeted areas in the brain to reduce or dispel debilitating symptoms of certain movement disorders, chronic pain, and some psychiatric conditions. Current DBS technology, while successfully used by many patients, does not always provide optimal benefit. The research being performed at the Bionics Institute aims to develop an innovative DBS system to treat disorders of the central nervous system using more advanced devices with improved fitting procedures and optimised stimulation parameters. These studies will assist in the development of the most efficient and effective treatment strategies for individual DBS users and contribute to a greater understanding of how positive therapeutic outcomes may be obtained with DBS.

Improving Clinical Outcomes by Optimising DBS for Essential Tremor

Essential Tremor is a progressive neurological disorder that causes involuntary shaking or trembling of particular parts of the body, usually the head and hands. The cause is unknown

although a strong genetic link is suggested. Although anyone of any age can develop Essential Tremor, older people are most predisposed with around one in five people over 65 years affected. It is therefore more prevalent than Parkinson’s disease. Deep brain stimulation provides moderate relief for approximately 90% of patients with Essential Tremor. Previous research has shown that precise electrode positioning and optimised selection of the stimulation parameters are important to obtain the greatest benefit with minimal side-effects for each patient. Adverse side-effects commonly include poor articulation of speech. The overall aim of this project is therefore to optimise device settings to provide immediate clinical benefits. We plan to achieve this by investigating how DBS parameters interact with each other to influence tremor using methods that improve clinical assessments of tremor severity. Using this knowledge and more accurate techniques we will conduct clinical studies that are planned to lead to commercial production of our device and its translation into clinical practice.

Participants in our investigations are adults diagnosed with Essential Tremor who use existing DBS systems. Analysis of data collected from patients indicates that

Small position sensors are placed on the patient’s hand to monitor pathological tremor using our specialised software. Tremor severity measurements can be used to set ideal levels of DBS.


careful selection of individual parameter values is necessary to achieve optimal performance of DBS for tremor reduction while avoiding undesirable side-effects. Preliminary findings have been presented at two conferences, and related articles for publication in peer-reviewed journals are under preparation. We have also developed and tested a computer-based system to assist clinicians in setting the DBS parameters that are optimal for each patient. This system is nearing completion. After further evaluation, we will consider how to commercialise it or find an alternative way of promoting its use in regular clinical practice.

In the past year:

— Software has been developed to accurately measure tremor and aid clinical assessment

— A voice analysis system is under development to assess voice tremor side-effects

— Approval was sought from the St Vincent’s Hospital ethics committee to extend clinical trials with patients who use DBS devices to alleviate tremor.

Research Team: Prof Hugh McDermott, Prof Colette McKay, Dr Thushara Perera and Mr Shivanthan Yohanandan.

External collaborators: Dr Richard Peppard and Ms Mary Jones (Precision Neurosurgery); Dr Adam Vogel (University of Melbourne); and Dr Andrew Evans (Flemington Neurology).

Funding: Colonial Foundation; St Vincent’s Research Endowment Fund.

Postural Stability in Patients with DBS for Parkinson’s Disease

Like Essential Tremor, Parkinson’s disease is a progressively degenerative neurological disorder which affects the control of body movements. Unlike Essential Tremor, Parkinson’s disease is not genetic. Parkinson’s disease occurs when nerve cells in a certain part of the brain die or become impaired. The inactivity of these cells results in the decrease of a messenger compound that controls smooth movement of muscles. When approximately 70% of the cells are inactive, the symptoms of Parkinson disease appear and will affect the individual for the remainder of their life, with increasing severity if left untreated. Approximately 1,000 new cases are diagnosed in Victoria

and 20,000 in Australia each year. Severity of Parkinson’s disease is often determined by subjective measures that may lead to inaccuracies. Research at the Bionics Institute therefore aims to develop devices and techniques to collect and measure the ability of Parkinson’s disease patients with DBS devices to remain upright. These results will provide an essential database for developing the most effective treatment strategies for each DBS user, and contribute to a greater understanding of how and why positive therapeutic results may be obtained with DBS. Specifically we aim to establish an evidence-based relationship between the

brain stimulation parameters of the device and patient balance.

Collection and analysis of data collected from DBS users who have Parkinson’s disease is continuing. These patients have electrodes placed in a brain region that has not previously been routinely used. A computer-based system similar to that under development for Essential Tremor is being developed and evaluated to simplify objective measurements of movement and gait disorders associated with Parkinson’s disease. Clinical studies to test and refine this system will commence shortly.


— Developed techniques to measure how the body responds to postural challenges

— Prepared for the clinical studies to evaluate these techniques with patients who use DBS to control symptoms of Parkinson’s disease (beginning in 2014).

Research Team: Prof Hugh McDermott, Prof Colette McKay, and Dr Thushara Perera.

External collaborators: Dr Wesley Thevathasan (University of Melbourne/ Royal Melbourne Hospital).

Funding: Colonial Foundation; Brain Foundation.

DBS for Obsessive-Compulsive Disorder (OCD)

Refractory obsessive-compulsive disorder (OCD) is characterised by disabling thoughts and behaviours that can be difficult to manage or eradicate. Conventional treatments rarely alleviate symptoms

The sway area calculated from the above graphs was used to quantify sway in patients with Parkinson’s disease (with and without DBS) compared to normal controls.

These experiments measured the ability of patients to remain upright by tracking their balance. The patient stands on a device that measures pressure applied to different areas and therefore measures postural sway.


Neurobionicscompletely, and about 30 per cent of patients remain refractory to treatment. DBS has been shown to reduce the severity of OCD symptoms in several exploratory trials overseas. A small group of adults with refractory OCD will be implanted in Melbourne with commercially available DBS devices and assessed using established subjective and objective measures. The optimal stimulation parameter settings required to alleviate symptoms will be established for each participant. In addition, these patients will undergo state-of-the-art imaging techniques to investigate the physiological effects of OCD and the DBS treatment. Results from this study will contribute to the design of innovative electrodes and optimised stimulators for future DBS devices under development at the Bionics Institute.

Conditional ethics approval was recently granted by the St Vincent’s Hospital Human Research Ethics Committee to evaluate commercial DBS devices as a treatment for refractory obsessive-compulsive disorder. Approvals are now required for each candidate patient through the Victorian Psychosurgery Review Board: the first potential participant has been identified, and upon approval by the review board, the first surgery will be scheduled to implant a

DBS device in 2014. During implantation, Bionics Institute researchers will perform electrical measurements that will inform the ongoing development of our innovative DBS systems. In addition, DBS settings will be optimised and behavioural outcomes assessed during the post-operative period.


— Gained approval by the St Vincent’s Hospital Human Research Ethics Committee to commence clinical studies testing DBS for treatment of obsessive-compulsive disorder (OCD)

— Sought approval from the Victorian Psychosurgery Review Board for each potential participant.

Research Team: Prof Hugh McDermott, Dr Leigh McKinlay, and Dr Amanda Walmsley.

External collaborators: Dr Peter Bosanac, Prof David Castle, and Prof Mark Cook (University of Melbourne/St Vincent’s Hospital Melbourne); Mr Peter McNeill (St Vincent’s Hospital Melbourne); Dr Susan Rossell (Swinburne University); and Dr James Olver (Austin Institute).

Funding: Colonial Foundation.

Development of DBS Electrodes and Implantation Procedures

Commercial DBS devices currently available are effective, but ongoing innovation at the Bionics Institute has led to technical improvements potentially enabling improved efficacy and safety. We are developing advanced bionic devices to maximise clinical benefit while minimising side-effects. We are developing and testing prototype electrodes that are able to target specific regions of the brain, thus minimising any adverse side-effects. Preclinical studies of experimental electrode arrays are being carried out to ensure that they can be surgically inserted without causing brain trauma, and that the electrical stimulation they deliver is safe.

Trials of innovative, prototype electrodes are in development and are planned for early 2014 in collaboration with the University of Melbourne. The prototype electrodes are smaller in order to induce less trauma during implantation and to enable targeting of more precise or smaller areas of the brain. A new percutaneous connector is also being designed to reduce the rate of infection often experienced with current

The prototype electrodes being developed are smaller than those in current commercial devices. These new electrodes will induce less trauma during implantation and enable targeting of smaller areas of the brain.

devices. These state-of-the-art designs will be implemented into innovative devices including DBS systems for movement disorders, psychiatric conditions, and pain alleviation.

In the past year we have developed:

— Innovative prototype electrodes

— An improved percutaneous connector system.

Research Team: Prof Hugh McDermott, Prof Rob Shepherd, A/Prof Chris Williams, Dr Joel Villalobos, Dr Warwick Nesbitt, Dr Olivier Bibari, Mr Owen Burns, Dr Thushara Perera, and Ms Lisa Cardamone.

External collaborators: Mr Peter McNeill (St Vincent’s Hospital Melbourne); Dr Sam Long (University of Melbourne); A/Prof Andrew Danks (Monash University); and Dr Richard Sullivan (Peter MacCallum Cancer Centre).

Funding: Colonial Foundation, Bionic Enterprises.

Peripheral nerve stimulation for treatment of chronic neuropathic painChronic neuropathic pain has a reported prevalence of up to 8% in the general population, with total costs in excess of 560 billion USD per annum in the USA. Furthermore, chronic pain is often refractory to state-of-the-art therapies including a range of pharmacological agents. Peripheral nerve stimulation has been proposed as an alternative, non-pharmacological therapy capable of providing long-term pain relief. However, the lack of well-established stimulation protocols and application-specific electrodes has prevented wide-spread application. This project will determine safe and effective stimulation regimes and develop peripheral nerve electrodes in order to achieve improved pain management therapies.

To facilitate the development of new peripheral nerve stimulation treatments, we developed a low-cost platform technology comprising of a small, battery-powered neural stimulator, a wireless patient controller in the form of a wrist watch,

Stimulation circuit of the wearable peripheral nerve stimulation system with wireless patient control.

and programming tools. The wearable stimulator is capable of addressing up to 12 electrodes via percutaneous leadwires and delivering stimulation using customised, freely configurable stimulation programs. The flexibility allows for application from preclinical studies to clinical trials in an outpatient setting. The platform will be used to test the safety and efficacy of novel electrode arrays for peripheral nerve stimulation, including the selective activation of peripheral nerve fascicles and novel stimulation paradigms for improved clinical outcomes in patients with chronic neuropathic pain.


— Developed a new clinical grade peripheral nerve stimulation platform

— Developed a patient controllable peripheral nerve stimulation platform

— Worked on the concept design of a new peripheral nerve stimulation array.

Research Team: Mr Philipp Senn (PhD student), Dr James Fallon and Prof Rob Shepherd.

External collaborators: Dr Jane Trinca, Dr Andrew Muir (St Vincent’s Hospital Melbourne).

Funding: Melbourne International Research Scholarship and a Melbourne International Fee Remission Scholarship to Mr Philipp Senn.



2013 Publications

Book Chapters1. Heil, P., Neubauer, H., Testschke, M., &

Irvine, D. R. F. (2013). A probabilistic account of absolute auditory thresholds and their possible physiological basis. In B. C. J. Moore, R. D. Patterson, I. Winter, R. P. Carlyon & H. E. Gockel (Eds.), Basic aspects of hearing: Physiology and perception (pp. 21-29). New York: Springer.

2. Kral, A., Baumhoff, P., & Shepherd, R. K. (2013). Integrative neuronal functions in deafness. In: Deafness. Vol 47 Springer Handbook of Auditory Research, A. Kral, F. Fay & A. Popper (Eds.), Deafness (pp. 151-187). New York: Springer.

3. Shepherd, R. K., Fallon, J. B., & McDermott, H. J. (in press). Medical bionics. In S.-A. Zhou & Z. Luwei (Eds.), Physical medicine and rehabilitation: Principles and applications.

4. Shepherd, R. K., Wise, A. K., & Fallon, J. B. (2013). Cochlear Implants. In G. Celesia (Ed.), Disorders of peripheral and central auditory processing (pp 315-331): Elsevier.

Articles1. Aram, P., Freestone, D. R., Dewar,

M., Scerri, K., Jirsa, V., Grayden, D. B. & Kadirkamanathan, V. (2013). Spatiotemporal multi-resolution approximation of the Amari type neural field model. NeuroImage, 66, 88-102.

2. Badawy, R. A. B., Badawy, A., Lai, A., Vogrin S. J. & Cook, M. J. (2013). Subcortical epilepsy? Neurology, 80, 1901-1907.

3. Badawy, R. A. B., Vogrin, S. J., Lai, A. & Cook, M. J. (2013). Capturing the epileptic trait: cortical excitability measures in patients and their unaffected siblings. Brain, 136, 1177-1191.

4. Badawy, R. A. B., Vogrin, S. J., Lai, A. & Cook, M. J. (2013). Cortical excitability changes correlate with fluctuations in glucose levels in patients with epilepsy. Epilepsy & behaviour, 27, 455-460.

5. Badawy, R. A. B., Vogrin, S. J., Lai, A. & Cook, M. J. (2013). Patterns of cortical hyperexcitability in adolescent/adult-onset generalized epilepsies. Epilepsia, 54, 871-878.

6. Barutchu, A., Freestone, D. R., Innes-Brown, H., Crewther, D. P. & Crewther, S. G. (2013). Evidence for Enhanced Multisensory Facilitation with Stimulus Relevance: An Electrophysiological Investigation. PLoS ONE, 8, e52978.

7. Benovitski, Y., Blamey, P., Rathbone, G. & Fallon, J. (in press). An automated psychoacoustic testing apparatus for use in cats. Hearing Research.

8. Blamey, P., Artieres, F., Baskent, D., Bergeron, F., Beynon, A., Burke, E., Dillier, N., Dowell, R., Fraysse, B., Gallégo, S., Govaerts, P. J., Green, K., Huber, A. M., Kleine-Punte, A., Maat, B., Marx, M., Mawman, D., Mosnier, I., O’Connor, A. F., O’Leary, S., Rousset, A., Schauwers, K., Skarzynski, H., Skarzynski, P. H., Sterkers, O., Terranti, A., Truy, E., Van de Heyning, P., Venail, F., Vincent, C. & Lazard, D. S. (2013). Factors affecting auditory performance of postlinguistically deaf adults using cochlear implants: An update with 2251 patients. Audiology Neurootology, 18, 36-47.

9. Fallon, J., Shepherd, R. & Irvine, D. (in press). Effects of chronic cochlear electrical stimulation after an extended period of profound deafness on primary auditory cortex organization in cats. European Journal of Neuroscience.

10. Fifer, J., Barutchu, A., Shivdasani, M. & Crewther, S. (2013). Verbal and novel multisensory associative learning in adults. F1000Research, 2, 34.

11. Francart, T., & McDermott, H. (2013). Psychophysics, fitting and signal processing for combined hearing aid and

cochlear implant stimulation. Ear and Hearing, 34(6):685-700.

12. Ganesan, K., Garrett, D. J., Ahnood, A., Shivdasani, M. N., Tong, W., Turnley, A. M., Fox, K., Meffin, H., & Prawer, S. (in press). An all-diamond, hermetic electrical feedthrough array for a retinal prosthesis. Hearing Research.

13. Halliday, A. J., Campbell, T. E., Nelson, T. S., McLean, K. J., Wallace, G. G. & Cook, M. J. (2013). Levetiracetam-loaded biodegradable polymer implants in the tetanus toxin model of temporal lobe epilepsy in rats. Journal of Clinical Neuroscience, 20, 148-152.

14. Henshall, K. R., Sergejew, A. A., Rance, G., McKay, C. M. & Copolov, D. L. (2013). Interhemispheric EEG coherence is reduced in auditory cortical regions in schizophrenia patients with auditory hallucinations. International Journal of Psychophysiology, 89, 63-71.

15. Hersbach, A., Grayden, D., Fallon, J. & McDermott, H. (2013). A beamformer post-filter for cochlear implant noise reduction. Journal of the Acoustical Society of America, 133, 2412-2420.

16. Holt, C. & McDermott, H. J. (2013). Discrimination of intonation contours by adolescents with cochlear implants. International Journal of Audiology, 52(12), 808-15.

17. Innes-Brown, H., Marozeau, J. M., Storey, C. M. & Blamey, P. J. (2013). Tone, rhythm, and timbre perception in school-aged children using cochlear implants and hearing aids. Journal of the American Academy of Audiology, 24, 789-806.

18. Innes-Brown, H., Barutchu, A., & Crewther, D. P. (2013). Neural responses in parietal and occipital areas in response to visual events are modulated by prior multisensory stimuli. PLoS One, 8, e84331.

19. Irving, S., Trotter, M. I., Fallon, J. B., Millard, R. E., Shepherd, R. K. & Wise, A. K. (2013). Cochlear implantation


for chronic electrical stimulation in the mouse. Hear Res, 306, 37-45.

20. John, S., Shivdasani, M. N., Williams, C. E., Morley, J. W., Shepherd, R., Rathbone, G. D. & Fallon, J. B. (2013). Suprachoroidal electrical stimulation: Effects of stimulus pulse parameters on visual cortical responses. Journal of Neural Engineering, 10.

21. Kaufmann, S. S., D. A., Hall, L. T., Perunicic, V., Senn, P., Steinert, S., McGuinness, L. P., Johnson, B. C., Ohshima, T., Caruso, F., Wrachtrup, J., Scholten, R. E., Mulvaney, P. & Hollenberg, L. C. L. (in press). Detection of atomic spin labels in a lipid bi-layer using a single-spin nanodiamond probe. Proceedings of the National Academy of Sciences of the United States of America.

22. Kerr, R. R., Burkitt, A. N., Thomas, D. A., Gilson, M. & Grayden, D. B. (2013). Delay selection by spike-timing-dependent plasticity in recurrent networks of spiking neurons receiving oscillatory inputs. PLoS Computational Biology, 9.

23. King, E. B., Hartsock, J. J., O’Leary, S. J. & Salt, A. N. (2013). Influence of cochleostomy and cochlear implant insertion on drug gradients following intratympanic application in guinea pigs. Audiol Neurotol, 18, 307-316.

24. King, E. B., Salt, A. N., Kel, G. E., Eastwood, H. T. & O’Leary, S. J. (2013). Gentamicin administration on the stapes footplate causes greater hearing loss and vestibulotoxicity than round window administration in guinea pigs. Hearing Research, 304, 159-166.

25. Landry, T. G., Fallon, J., Wise, A. & Shepherd, R. (2013). Chronic neurotrophin delivery promotes ectopic neurite growth from the spiral ganglion of deafened cochleae without compromising the spatial selectivity of cochlear implants. J Comp Neurol, 521, 2818-2832.

26. Lazard, D. S., Innes-Brown, H. & Barone, P. (in press). Adaptation of the communicative brain to post-lingual deafness. Evidence from functional imaging. Hearing Research.

27. Maarefvand, M., Marozeau, J. & Blamey, P. J. (2013). A cochlear implant user with exceptional musical hearing ability. International Journal of Audiology, 52, 424-432.

28. Marozeau, J. M., Innes-Brown, H. & Blamey, P. J. (2013). The acoustic and perceptual cues affecting melody

segregation for listeners with a cochlear implant. Frontiers in Psychology, 4, article 790.

29. Marozeau, J. M., Innes-Brown, H. & Blamey, P. J. (2013). The effect of timbre and loudness on melody segregation. Music Perception, 30, 259-274.

30. Nayagam, B. A., Edge, A. S., Needham, K., Hyakumura, T., Leung, J., Nayagam, D. A. X. & Dottori, M. (2013). An In Vitro Model of Developmental Synaptogenesis Using Cocultures of Human Neural Progenitors and Cochlear Explants. Stem Cells and Development, 22(6), 901-912.

31. Nayagam, D. A. X., McGowan, C., Villalobos, J., Williams, R. A., Salinas-LaRosa, C., McKelvie, P., Lo, I., Basa, M., Tan, J. & Williams, C. E. (2013). Techniques for processing eyes implanted with a retinal prosthesis for localized histopathological analysis. Journal of visualized experiments: JoVE, 78.

32. Needham, K., Hyakumura, T., Gunewardene, N., Dottori, M. & Nayagam, B. (in press). Electrophysiological properties of neurosensory progenitors derived from human embryonic stem cells. Stem Cell Research.

33. Needham, K., Minter, R. L., Shepherd, R. & Nayagam, B. A. (2013). Challenges for stem cells to functionally repair the damaged auditory nerve. Expert Opinion on Biological Therapy, 13, 85-101.

34. Newbold, C., Mergen, S., Richardson, R., Seligman, P., Millard, R., Cowan, R. & Shepherd, R. (in press). Impedance changes in chronically implanted and stimulated cochlear implant electrodes. Cochlear implants international.

35. O’Leary, S. J., Monksfield, P., Kel, G., Connolly, T., Souter, M. A., Chang, A., Marovic, P., O’Leary, J. S., Richardson, R. & Eastwood, H. (2013). Relations between cochlear histopathology and hearing loss in experimental cochlear implantation. Hearing Research, 298, 27-35.

36. Rickard, N. A., Heidtke, U. J. & O’Beirne, G. A. (2013). Assessment of auditory processing in children using an adaptive filtered speech test. International Journal of Audiology, 52, 687-697.

37. Rickard, N. A., Smales, C. J. & Rickard, K. L. (2013). A computer-based auditory sequential pattern test for school-

aged children. International Journal of Pediatric Otorhinolaryngology, 77, 838–842.

38. Saunders, A. L., Williams, C. E., Heriot, W., Briggs, R., Yeoh, J., Nayagam, D. A. X., McCombe, M., Villalobos, J., Burns, O., Luu, C. D., Ayton, L. N., McPhedran, M., Opie, N. L., McGowan, C., Shepherd, R. K., Guymer, R., & Allen, P. J. (in press). Development of a surgical procedure for implantation of a prototype suprachoroidal retinal prosthesis. Clinical and Experimental Ophthalmology.

39. Savage, C. O., Grayden, D. B., Meffin, H. & Burkitt, A. N. (2013). Optimized single pulse stimulation strategy for retinal implants. Journal of Neural Engineering, 10, e16003.

40. Shepherd, R. K., Shivdasani, M. N., Nayagam, D. A. X., Williams, C. E. & Blamey, P. J. (2013). Visual prostheses for the blind. Trends in Biotechnology, 31, 562-571.

41. Varsavsky, A. & McDermott, H. (2013). Application of real-time loudness models can improve speech recognition for cochlear implant users. IEEE in Transactions on Neural Systems & Rehabilitation Engineering, 21, 81-87.

42. Villalobos, J., Nayagam, D. A. X., Allen, P. J., McKelvie, P., Luu, C. D., Ayton, L., Freemantle, A., McPhedran, M., Basa, M., McGowan, C., Shepherd, R. & Williams, C. E. (2013). A wide-field suprachoroidal retinal prosthesis is stable and well tolerated following chronic implantation. Investigative Ophthalmology and Visual Science, 54, 3751-3762.

43. Wade, S. A., Fallon, J.B., Wise, A. K., Shepherd, R. K., James, N. L., & Stoddart, P. R. (in press). Measurement of forces at the tip of a cochlear implant insertion. IEEE Transactions in Biomedical Engineering.


Conference PresentationsAustralian Neuroscience Society, 33rd Annual Meeting, Jan 2013

Cell-based neurotrophin delivery for auditory neuron survival in deafness. Gillespie, L., Zanin, M.P. & Shepherd, R.K.

Spatiotemporal interactions in the visual cortex using paired electrical stimulation of the retina. Cicione, R., Shivdasani, M.N., Fallon, J.B., Rathbone, G.D. & Williams, C.E.

Suprachoroidal electrical stimulation: assessing efficacy of repetitive electrical stimulation. John, S., Shivdasani, M.N., Fallon, J.B., Rathbone, G. & Williams, C.W.

Epiretinal stimulation using ultrananocrystalline diamond electrodes Shivdasani, M., Garrett, D.J., Nayagam, D.A.X., Allen, P.J., Saunders, A., McPhedran, M., Burns, O., Meffin, H., Prawer, S. & Shepherd, R.K.

Novel method for determining frequency discrimination abilities of cats without using negative reinforcement Benovitski, Y., Fallon, J.B., Blamey, P.J. & Rathbone, G.D.

Regeneration and protection in the deaf cochlea. Atkinson, P., Wise, A.K., Flynn, B.O., Nayagam, B.A., Hume, C.R., O’Leary, S.J., Shepherd, R.K. & Richardson, R.T.

The feasibility of explanting a suprachoroidal electrode array in a feline model. Leung, Ronald, Nayagam, D., Williams, R., Allen, P., Salinas-La Rosa, C., Luu C., Ayton, L., Basa, M., Yeoh, J., Shepherd, R. & Williams, C.

Cochlear implant use causes changes in the cochleotopic organisation of auditory cortex. Irving, S., Irvine, D.R.F., Shepherd, R.K. & Fallon, J.B.

Effects of age on the preservation of residual hearing with cochlear implants. Wise, A.K., Irving, S., Shepherd, R.K. & Fallon, J.B.

Halting the Progression of Noise-Induced Hearing Loss with Gene Therapy. Richardson, R. T., Atkinson, P., Wise, A. K., Flynn, B. O., O’Leary, S. J., Hume, C. J. & Shepherd, R. K.

NeuroEng 2013, 6th Australian Workshop on Computational Neuroscience, Melbourne, Jan 2013

Potential for Optimising Deep Brain Stimulation through tremor quantification

Perera, T., McKay, C. M., Peppard, R., McDermott, H. J., & Vogel, A.

Pitch recognition using Auditory Model Input Erfanian, N., Blamey, P., Burkitt, A. N., & Grayden, D. B.

Tracking physiological changes in the brain using a neural mass model. Balson, R., Freestone, D., Grayden, D. B., Burkitt, A. N., Blamey, P., & Cook, M. J.

Thirty-Sixth Annual Midwinter Research Meeting of the Association for Research in Otolaryngology, Baltimore, MD, Feb 2013

Cochlear implant use causes changes in the cochleotopic organisation of auditory cortex. Irving, S., Irvine, D.R.F., Shepherd, R.K., & Fallon, J.B.

Effects of age on the preservation of residual hearing with cochlear implants. Wise, A.K., Irving, S., Shepherd, R.K., & Fallon, J.B.

The Effects of Neurotrophins and Chronic Electrical Stimulation Delivered to the Deafened Guinea Pig Cochlea. Wise, A. K., Pujol, R., Landry, T., Fallon, J. B., & Shepherd, R. K.

A New Method for Determining Frequency Discrimination in Cats with Different Hearing Profiles. Benovitski, Y., Fallon, J. Blamey, P., & Rathbone, G.

Australasian Auditory Neuroscience Workshop, Melbourne Feb 2013

Cochlear implant use causes changes in the cochleotopic organisation of auditory cortex in deaf animals. Irving, S., Irvine, D., Shepherd, R. & Fallon, J.

Evaluation of phased array current-focusing strategies in animal models. George S.S., Fallon J.B., Wise A.K., Shivdasani M.N., & Shepherd R.K.

Cell-based neurotrophin treatment for auditory neuron survival. Gillespie, L., Zanin, M., & Shepherd, R.

38th International Conference on Acoustics, Speech, and Signal Processing (ICASSP), May 2013

Comparing monopolar with all-polar stimulation mode. Marozeau, J., McDermott, H. J., Swanson, B. A., & McKay, C. M.

Algorithms to improve listening in noise for cochlear implant users. Hersbach, A. A., Mauger, S. J., Grayden, D.

B., Fallon, J. B., & McDermott, H. J.

Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO), May 2013

Psychophysics of a suprachoroidal retinal prosthesis. Blamey, P., Sinclair, N., Slater, K., McDermott, H., Shivdasani, M., & Perera, T.

The Feasibility of Explanting a Suprachoroidal Electrode Array in a Feline Model. Leung, R. T., Nayagam, D. A. X., Williams, R. A., Allen, P. J., Salinas-La Rosa, C. M., Luu, C. D., Ayton, L. N., Basa, M., Shepherd, R. K., & Williams, C. E.

Development of a surgical procedure for implanting a wide view electrode array in the suprachoroidal space. Yeoh, J., Saunders, A., Nayagam, D. A. X., Williams, C. E., McCombe, M., Owen, B., Villalobos, J., McPhedran, M., Briggs, R., & Allen, P. J.

In Vivo Electrical Stimulation of a Retinal Prosthesis Containing Conductive Diamond Electrodes. Shivdasani, M. N., Garrett, D., J., Nayagam, D. A. X., Villalobos, J., Allen, P. J., Saunders, A., McPhedran, M., McGowan, C., Meffin, H., & Shepherd, R. K.

A Suprachoroidal Retinal Prosthesis with a Flexible Lead is Reliable for Patient Testing. Villalobos, J., Allen, P. J., Luu, C., Ayton, L. N., Yeoh, J., Nayagam, D. A. X., Opie, N. L., Shivdasani, M. N., Shepherd, R. K., & Williams, C. E.

Decrease in electrode-retina distance over time and its effect on electrical impedances in a suprachoroidal retinal prosthesis. Ayton, L. N., Sinclair, N. C., Blamey, P. J., Perera, T., Nayagam, D. A. X., Dimitrov, P. N., Allen, P. J., Varsamidis, M., Guymer, N. H., & Luu, C. D.

DARPA Neural Interfaces Symposium, Melbourne, May 2013

Research and Clinical Applications of Medical Bionics. Shepherd, R. K. – Invited speaker.

Centre for Brain Research Seminar, Auckland, New Zealand, June 2013

Neural prostheses: practical applications in neuroscience. Shepherd, R. K. – Invited speaker.

Conference on Implantable Auditory Prostheses (CIAP), July 2013

Comparing monopolar with multipolar stimulation modes. Marozeau, J, McDermott, H. J., Swanson, B. A., & McKay, C.M.


Temporal information processing: can current focusing help? McKay, C. M., Fielden, C. A., Marozeau, J., Kluk, K., McDermott, H. J.

Effects of chronic electro-acoustic stimulation on cortical responses. Fallon, J., Irving, S., Wise, A., Shepherd, R., McDermott, H., & Irvine, D.

Improved aesthetic responses to music in bimodal and bilateral cochlear implant users. Innes-Brown, H., Vannson, N., Peretz, I., & Marozeau J.

Sound processing to improve transmission of interaural level differences with combined cochlear implant and hearing aid stimulation. Francart, T., & McDermott, H.

Visual prostheses: a progress report for the CIAP community. Shepherd, R. K. – Invited speaker.

The Aikenhead Centre for Medical Discovery Research Week, Melbourne, Australia, August 2013

Development of Objective Tremor-Severity Measurement Software to Advise Clinicians during Deep Brain Stimulation Programming. Perera, T., Yohanandan, S. A. C., McDermott, H. J., & McKay, C. M.

Can suprachoroidal arrays be safely replaced? Leung, R., Nayagam, D. A. X., Williams, R., Allen, P., Salinas-La Rosa, C., Luu, C., Shivdasani, M., Ayton, L., Basa, M., Yeoh, J., Saunders, A., Shepherd, R., & Williams, C.

Cochlear implant use causes changes in the cochleotopic organisation of the auditory cortex in deaf animals. Irving, S., Irvine, D. R. F., Shepherd, R. K., & Fallon, J. B.

Cell-based neurotrophin delivery for auditory neuron survival in deafness. Gillespie, L. N., Zanin, M. P., & Shepherd, R. K.

Australasian Winter Conference on Brain Research, Queenstown, New Zealand, August 2013

Medical Bionics: Neural Interfaces for damaged nerves. Shepherd, R. K. – Invited speaker.

St Vincent’s Surgical Forum, Melbourne, August 2013

Sir Hugh Devine Oration “From the ear to eye – A short distance but a long journey.” Shepherd, R. K. – Invited speaker.

Edinburgh International Festival, Edinburgh, United Kingdom, August, 2013

The new Leonardos: art/science collaborations in Australia. Innes-Brown, H. – Invited speaker.

Tech Transfer Summit, Walter and Eliza Hall Institute, Melbourne, Australia, September, 2013

Bionic Eye. Blamey, P. J.

Third International Conference of Medical Bionics: Engineering Solutions for Neural Disorders, Phillip Island, Australia, November, 2013

Psychophysical And Vision Processing Results With A Prototype Suprachorodial Retinal Prosthesis. Blamey, P.J.

Medical Bionics Device Design: Its History and Future. McDermott, H.J.

Gene therapy for the protection and restoration of cochlear sensory cells after noise induced hearing loss. Richardson, R.

Cell-based neurotrophin delivery for auditory neuron survival in deafness. Gillespie, L.

Drug delivery to the inner ear for nerve survival. Wise, A.

Comparing all-polar with monopolar stimulation modes in cochlear implants. Marozeau, J.

Development of a flexible lead for a suprachoroidal retinal prosthesis. Villalobos, J.

Preclinical safety and efficacy of a bionic eye. Nayagam, D.

Shape, location and overlap of phosphenes elicited using a suprachoroidal electrode array. Sinclair, N.

Graphical user interface for bionic eye psychophysics. Perera, T.

Cochlear implant use causes changes in the cochleotopic organisation of the auditory cortex in deaf animals. Irving, S.

Improved aesthetic responses to music in bimodal and bilateral cochlear implant users. Innes-Brown, H.

New music for the Bionic Ear. An assessment of the enjoyment of six new works composed for cochlear implant recipients. Innes-Brown, H.

Gene therapy for the protection and restoration of cochlear sensory cells after noise-induced hearing loss. Richardson, R. T.

Optimising electrode stimulation and image processing parameters in a suprachoroidal retinal prosthesis using a pattern recognition task. Petoe, M. A.

Inaugural music, mind and health conference, Melbourne, Australia, November, 2013

The new Leonardo’s: New music for the bionic ear. Innes-Brown, H.

Bimodal and bilateral cochlear implant users prefer fast tempos: aesthetic responses to dichotic, binaural and monaural melodies. Marozeau, J.

Melbourne Brain Centre Neuroscience Seminar Series

The new Leonardos-art/science collaborations in Australia. Innes-Brown, H. – Invited speaker.

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