Publications by authors named "James B Fallon"

77 Publications

Viral-mediated transduction of auditory neurons with opsins for optical and hybrid activation.

Sci Rep 2021 May 27;11(1):11229. Epub 2021 May 27.

The Bionics Institute, East Melbourne, VIC, 3002, Australia.

Optical stimulation is a paradigm-shifting approach to modulating neural activity that has the potential to overcome the issue of current spread that occurs with electrical stimulation by providing focused stimuli. But optical stimulation either requires high power infrared light or genetic modification of neurons to make them responsive to lower power visible light. This work examines optical activation of auditory neurons following optogenetic modification via AAV injection in two species (mouse and guinea pig). An Anc80 viral vector was used to express the channelrhodopsin variant ChR2-H134R fused to a fluorescent reporter gene under the control of the human synapsin-1 promoter. The AAV was administered directly to the cochlea (n = 33) or posterior semi-circular canal of C57BL/6 mice (n = 4) or to guinea pig cochleae (n = 6). Light (488 nm), electrical stimuli or the combination of these (hybrid stimulation) was delivered to the cochlea via a laser-coupled optical fibre and co-located platinum wire. Activation thresholds, spread of activation and stimulus interactions were obtained from multi-unit recordings from the central nucleus of the inferior colliculus of injected mice, as well as ChR2-H134R transgenic mice (n = 4). Expression of ChR2-H134R was examined by histology. In the mouse, transduction of auditory neurons by the Anc80 viral vector was most successful when injected at a neonatal age with up to 89% of neurons transduced. Auditory neuron transductions were not successful in guinea pigs. Inferior colliculus responses to optical stimuli were detected in a cochleotopic manner in all mice with ChR2-H134R expression. There was a significant correlation between lower activation thresholds in mice and higher proportions of transduced neurons. There was no difference in spread of activation between optical stimulation and electrical stimulation provided by the light/electrical delivery system used here (optical fibre with bonded 25 µm platinum/iridium wire). Hybrid stimulation, comprised of sub-threshold optical stimulation to 'prime' or raise the excitability of the neurons, lowered the threshold for electrical activation in most cases, but the impact on excitation width was more variable compared to transgenic mice. This study demonstrates the impact of opsin expression levels and expression pattern on optical and hybrid stimulation when considering optical or hybrid stimulation techniques for neuromodulation.
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http://dx.doi.org/10.1038/s41598-021-90764-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160204PMC
May 2021

Provision of interaural time difference information in chronic intracochlear electrical stimulation enhances neural sensitivity to these differences in neonatally deafened cats.

Hear Res 2021 Jul 23;406:108253. Epub 2021 Apr 23.

Bionics Institute, Melbourne, Victoria, Australia; Medical Bionics Department, University of Melbourne, Melbourne, Victoria, Australia.. Electronic address:

Although performance with bilateral cochlear implants is superior to that with a unilateral implant, bilateral implantees have poor performance in sound localisation and in speech discrimination in noise compared to normal hearing subjects. Studies of the neural processing of interaural time differences (ITDs) in the inferior colliculus (IC) of long-term deaf animals, show substantial degradation compared to that in normal hearing animals. It is not known whether this degradation can be ameliorated by chronic cochlear electrical stimulation, but such amelioration is unlikely to be achieved using current clinical speech processors and cochlear implants, which do not provide good ITD cues. We therefore developed a custom sound processor to deliver salient ITDs for chronic bilateral intra-cochlear electrical stimulation in a cat model of neonatal deafness, to determine if long-term exposure to salient ITDs would prevent degradation of ITD processing. We compared the sensitivity to ITDs in cochlear electrical stimuli of neurons in the IC of cats chronically stimulated with our custom ITD-aware sound processor with sensitivity in acutely deafened cats with normal hearing development and in cats chronically stimulated with a clinical stimulator and sound processor. Animals that experienced stimulation with our custom ITD-aware sound processor had significantly higher neural sensitivity to ITDs than those that received stimulation from clinical sound processors. There was no significant difference between animals received no stimulation and those that received stimulation from clinical sound processors, consistent with findings from clinical cochlear implant users. This result suggests that development and use of clinical ITD-aware sound processing strategies from a young age may promote ITD sensitivity in the clinical population.
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http://dx.doi.org/10.1016/j.heares.2021.108253DOI Listing
July 2021

Platinum dissolution and tissue response following long-term electrical stimulation at high charge densities.

J Neural Eng 2021 Feb 12. Epub 2021 Feb 12.

Bionics Institute, 384-388 Albert Street East, Melbourne, Vic 3002, Fitzroy, Victoria, 3056, AUSTRALIA.

Objective: Established guidelines for safe levels of electrical stimulation for neural prostheses are based on a limited range of the stimulus parameters used clinically. Recent studies have reported particulate platinum (Pt) associated with long-term clinical use of these devices, highlighting the need for more carefully defined safety limits. We previously reported no adverse effects of Pt corrosion products in the cochleae of guinea pigs following 4 weeks of electrical stimulation using charge densities far greater than the published safe limits for cochlear implants. The present study examines the histopathological effects of Pt within the cochlea following continuous stimulation at a charge density well above the defined safe limits for periods up to 6 months.

Approach: Six cats were bilaterally implanted with Pt electrode arrays and unilaterally stimulated using charge balanced current pulses at a charge density of 267 C/cm2/phase using a tripolar electrode configuration. Electrochemical measurements were made throughout the implant duration and evoked potentials recorded at the outset and on completion of the stimulation program. Cochleae were examined histologically for particulate Pt, tissue response, and auditory nerve survival; electrodes were examined for surface corrosion; and cochlea, brain, kidney, and liver tissue analysed for trace levels of Pt.

Main Results: Chronic stimulation resulted in both a significant increase in tissue response and particulate Pt within the tissue capsule surrounding the electrode array compared with implanted, unstimulated control cochleae. Importantly, there was no stimulus-induced loss of auditory neurons or increase in evoked potential thresholds. Stimulated electrodes were significantly more corroded compared with unstimulated electrodes. Trace analysis revealed Pt in both stimulated and control cochleae although significantly greater levels were detected within stimulated cochleae. There was no evidence of Pt in brain or liver; however, trace levels of Pt were recorded in the kidneys of two animals. Finally, increased charge storage capacity and charge injection limit reflected the more extensive electrode corrosion associated with stimulated electrodes.

Significance: Long-term electrical stimulation of Pt electrodes at a charge density well above existing safety limits and nearly an order of magnitude higher than levels used clinically, does not adversely affect the auditory neuron population or reduce neural function, despite a stimulus-induced tissue response and the accumulation of Pt corrosion product. The mechanism resulting in Pt within the unstimulated cochlea is unclear, while the level of Pt observed systemically following stimulation at these very high charge densities does not appear to be of clinical significance.
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http://dx.doi.org/10.1088/1741-2552/abe5baDOI Listing
February 2021

Recording of Electrically Evoked Neural Activity and Bladder Pressure Responses in Awake Rats Chronically Implanted With a Pelvic Nerve Array.

Front Neurosci 2020 17;14:619275. Epub 2020 Dec 17.

Bionics Institute, Fitzroy, VIC, Australia.

Bioelectronic medical devices are well established and widely used in the treatment of urological dysfunction. Approved targets include the sacral S3 spinal root and posterior tibial nerve, but an alternate target is the group of pelvic splanchnic nerves, as these contain sacral visceral sensory and autonomic motor pathways that coordinate storage and voiding functions of the bladder. Here, we developed a device suitable for long-term use in an awake rat model to study electrical neuromodulation of the pelvic nerve (homolog of the human pelvic splanchnic nerves). In male Sprague-Dawley rats, custom planar four-electrode arrays were implanted over the distal end of the pelvic nerve, close to the major pelvic ganglion. Electrically evoked compound action potentials (ECAPs) were reliably detected under anesthesia and in chronically implanted, awake rats up to 8 weeks post-surgery. ECAP waveforms showed three peaks, with latencies that suggested electrical stimulation activated several subpopulations of myelinated A-fiber and unmyelinated C-fiber axons. Chronic implantation of the array did not impact on voiding evoked in awake rats by continuous cystometry, where void parameters were comparable to those published in naïve rats. Electrical stimulation with chronically implanted arrays also induced two classes of bladder pressure responses detected by continuous flow cystometry in awake rats: voiding contractions and non-voiding contractions. No evidence of tissue pathology produced by chronically implanted arrays was detected by immunohistochemical visualization of markers for neuronal injury or noxious spinal cord activation. These results demonstrate a rat pelvic nerve electrode array that can be used for preclinical development of closed loop neuromodulation devices targeting the pelvic nerve as a therapy for neuro-urological dysfunction.
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http://dx.doi.org/10.3389/fnins.2020.619275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773906PMC
December 2020

Oculomotor Responses to Dynamic Stimuli in a 44-Channel Suprachoroidal Retinal Prosthesis.

Transl Vis Sci Technol 2020 12 18;9(13):31. Epub 2020 Dec 18.

Bionics Institute, East Melbourne, Australia.

Purpose: To investigate oculomotor behavior in response to dynamic stimuli in retinal implant recipients.

Methods: Three suprachoroidal retinal implant recipients performed a four-alternative forced-choice motion discrimination task over six sessions longitudinally. Stimuli were a single white bar ("moving bar") or a series of white bars ("moving grating") sweeping left, right, up, or down across a 42″ monitor. Performance was compared with normal video processing and scrambled video processing (randomized image-to-electrode mapping to disrupt spatiotemporal structure). Eye and head movement was monitored throughout the task.

Results: Two subjects had diminished performance with scrambling, suggesting retinotopic discrimination was used in the normal condition and made smooth pursuit eye movements congruent to the moving bar stimulus direction. These two subjects also made stimulus-related eye movements resembling optokinetic reflex (OKR) for moving grating stimuli, but the movement was incongruent with stimulus direction. The third subject was less adept at the task, appeared primarily reliant on head position cues (head movements were congruent to stimulus direction), and did not exhibit retinotopic discrimination and associated eye movements.

Conclusions: Our observation of smooth pursuit indicates residual functionality of cortical direction-selective circuits and implies a more naturalistic perception of motion than expected. A distorted OKR implies improper functionality of retinal direction-selective circuits, possibly due to retinal remodeling or the non-selective nature of the electrical stimulation.

Translational Relevance: Retinal implant users can make naturalistic eye movements in response to moving stimuli, highlighting the potential for eye tracker feedback to improve perceptual localization and image stabilization in camera-based visual prostheses.
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http://dx.doi.org/10.1167/tvst.9.13.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757638PMC
December 2020

Laminin coated diamond electrodes for neural stimulation.

Mater Sci Eng C Mater Biol Appl 2021 Jan 27;118:111454. Epub 2020 Aug 27.

School of Physics, The University of Melbourne, Parkville, Melbourne, VIC 3010, Australia; RMIT University, School of Engineering, Melbourne, VIC 3001, Australia.

The performance of many implantable neural stimulation devices is degraded due to the loss of neurons around the electrodes by the body's natural biological responses to a foreign material. Coating of electrodes with biomolecules such as extracellular matrix proteins is one potential route to suppress the adverse responses that lead to loss of implant functionality. Concurrently, however, the electrochemical performance of the stimulating electrode must remain optimal to continue to safely provide sufficient charge for neural stimulation. We have previously found that oxygen plasma treated nitrogen included ultrananocrystalline diamond coated platinum electrodes exhibit superior charge injection capacity and electrochemical stability for neural stimulation (Sikder et al., 2019). To fabricate bioactive diamond electrodes, in this work, laminin, an extracellular matrix protein known to be involved in inter-neuron adhesion and recognition, was used as an example biomolecule. Here, laminin was covalently coupled to diamond electrodes. Electrochemical analysis found that the covalently coupled films were robust and resulted in minimal change to the charge injection capacity of diamond electrodes. The successful binding of laminin and its biological activity was further confirmed using primary rat cortical neuron cultures, and the coated electrodes showed enhanced cell attachment densities and neurite outgrowth. The method proposed in this work is versatile and adaptable to many other biomolecules for producing bioactive diamond electrodes, which are expected to show reduced the inflammatory responses in vivo.
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http://dx.doi.org/10.1016/j.msec.2020.111454DOI Listing
January 2021

Objective measurement of tinnitus using functional near-infrared spectroscopy and machine learning.

PLoS One 2020 18;15(11):e0241695. Epub 2020 Nov 18.

The Bionics Institute, East Melbourne, Victoria, Australia.

Chronic tinnitus is a debilitating condition which affects 10-20% of adults and can severely impact their quality of life. Currently there is no objective measure of tinnitus that can be used clinically. Clinical assessment of the condition uses subjective feedback from individuals which is not always reliable. We investigated the sensitivity of functional near-infrared spectroscopy (fNIRS) to differentiate individuals with and without tinnitus and to identify fNIRS features associated with subjective ratings of tinnitus severity. We recorded fNIRS signals in the resting state and in response to auditory or visual stimuli from 25 individuals with chronic tinnitus and 21 controls matched for age and hearing loss. Severity of tinnitus was rated using the Tinnitus Handicap Inventory and subjective ratings of tinnitus loudness and annoyance were measured on a visual analogue scale. Following statistical group comparisons, machine learning methods including feature extraction and classification were applied to the fNIRS features to classify patients with tinnitus and controls and differentiate tinnitus at different severity levels. Resting state measures of connectivity between temporal regions and frontal and occipital regions were significantly higher in patients with tinnitus compared to controls. In the tinnitus group, temporal-occipital connectivity showed a significant increase with subject ratings of loudness. Also in this group, both visual and auditory evoked responses were significantly reduced in the visual and auditory regions of interest respectively. Naïve Bayes classifiers were able to classify patients with tinnitus from controls with an accuracy of 78.3%. An accuracy of 87.32% was achieved using Neural Networks to differentiate patients with slight/ mild versus moderate/ severe tinnitus. Our findings show the feasibility of using fNIRS and machine learning to develop an objective measure of tinnitus. Such a measure would greatly benefit clinicians and patients by providing a tool to objectively assess new treatments and patients' treatment progress.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241695PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673524PMC
January 2021

Hybrid optogenetic and electrical stimulation for greater spatial resolution and temporal fidelity of cochlear activation.

J Neural Eng 2020 11 4;17(5):056046. Epub 2020 Nov 4.

The Bionics Institute, East Melbourne, VIC, 3002, Australia.

Objective: Compared to electrical stimulation, optogenetic stimulation has the potential to improve the spatial precision of neural activation in neuroprostheses, but it requires intense light and has relatively poor temporal kinetics. We tested the effect of hybrid stimulation, which is the combination of subthreshold optical and electrical stimuli, on spectral and temporal fidelity in the cochlea by recording multiunit activity in the inferior colliculus of channelrhodopsin (H134R variant) transgenic mice.

Approach: Pulsed light or biphasic electrical pulses were delivered to cochlear spiral ganglion neurons of acutely deafened mice, either as individual stimuli or as hybrid stimuli for which the timing of the electrical pulse had a varied delay relative to the start of the optical pulse. Response thresholds, spread of activation and entrainment data were obtained from multi-unit recordings from the auditory midbrain.

Main Results: Facilitation occurred when subthreshold electrical stimuli were applied at the end of, or up to 3.75 ms after subthreshold optical pulses. The spread of activation resulting from hybrid stimulation was significantly narrower than electrical-only and optical-only stimulation (p < 0.01), measured at equivalent suprathreshold levels of loudness that are relevant to cochlear implant users. Furthermore, temporal fidelity, measured as maximum following rates to 300 ms pulse trains bursts up to 240 Hz, was 2.4-fold greater than optical-only stimulation (p < 0.05).

Significance: By significantly improving spectral resolution of electrical- and optical-only stimulation and the temporal fidelity of optical-only stimulation, hybrid stimulation has the potential to increase the number of perceptually independent stimulating channels in a cochlear implant.
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http://dx.doi.org/10.1088/1741-2552/abbff0DOI Listing
November 2020

Chronic intracochlear electrical stimulation at high charge densities: reducing platinum dissolution.

J Neural Eng 2020 10 8;17(5):056009. Epub 2020 Oct 8.

Bionics Institute, St Vincent's Hospital, Melbourne, Australia. Medical Bionics Department, The University of Melbourne, Melbourne, Australia.

Objective: Cochleae of long-term cochlear implant users have shown evidence of particulate platinum (Pt) corroded from the surface of Pt electrodes. The pathophysiological effect of Pt within the cochlea has not been extensively investigated. We previously evaluated the effects of Pt corrosion at high charge densities and reported negligible pathophysiological impact. The present study extends this work by examining techniques that may reduce Pt corrosion.

Approach: Deafened guinea pigs were continuously stimulated for 28 d using biphasic current pulses at extreme charge densities using: (i) electrode shorting; (ii) electrode shorting with capacitive coupling (CC); or (iii) electrode shorting with alternating leading phase (AP). On completion of stimulation, cochleae were examined for corrosion product, tissue response, auditory nerve (AN) survival and trace levels of Pt; and electrodes examined for surface corrosion.

Main Results: Pt corrosion was evident at ≥200 μC cm phase; the amount dependent on charge density (p< 0.01) and charge recovery technique (p < 0.01); reduced corrosion was apparent using CC. Tissue response increased with charge density (p< 0.007); cochleae stimulated at ≥200 μC cm phase exhibited a vigorous response including a focal region of necrosis and macrophages. Notably, tissue response was not dependent on the charge recovery technique (p = 0.56). Despite stimulation at high charge densities resulting in significant levels of Pt corrosion, there was no stimulus induced loss of ANs.

Significance: Significant increases in tissue response and Pt corrosion were observed following stimulation at high charge densities. Charge recovery using CC, and to a lesser extent AP, reduced the amount of Pt corrosion but not the tissue response. Stimulation at change densities an order of magnitude higher than those used when programming cochlear implant recipients in the clinic, produced a vigorous tissue response and corrosion products without evidence of neural loss.
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http://dx.doi.org/10.1088/1741-2552/abb7a6DOI Listing
October 2020

Optical stimulation of neural tissue.

Healthc Technol Lett 2020 Jun 25;7(3):58-65. Epub 2020 Jun 25.

Bionics Institute, Melbourne 3002, Australia.

Electrical stimulation has been used for decades in devices such as pacemakers, cochlear implants and more recently for deep brain and retinal stimulation and electroceutical treatment of disease. However, current spread from the electrodes limits the precision of neural activation, leading to a low quality therapeutic outcome or undesired side-effects. Alternative methods of neural stimulation such as optical stimulation offer the potential to deliver higher spatial resolution of neural activation. Direct optical stimulation is possible with infrared light, while visible light can be used to activate neurons if the neural tissue is genetically modified with a light sensitive ion channel. Experimentally, both methods have resulted in highly precise stimulation with little spread of activation at least in the cochlea, each with advantages and disadvantages. Infrared neural stimulation does not require modification of the neural tissue, but has very high power requirements. Optogenetics can achieve precision of activation with lower power, but only in conjunction with targeted insertion of a light sensitive ion channel into the nervous system via gene therapy. This review will examine the advantages and limitations of optical stimulation of neural tissue, using the cochlea as an exemplary model and recent developments for retinal and deep brain stimulation.
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http://dx.doi.org/10.1049/htl.2019.0114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353819PMC
June 2020

Differential effects of vagus nerve stimulation strategies on glycemia and pancreatic secretions.

Physiol Rep 2020 06;8(11):e14479

Bionics Institute, East Melbourne, Vic., Australia.

Despite advancements in pharmacotherapies, glycemia is poorly controlled in type 2 diabetic patients. As the vagus nerve regulates energy metabolism, here we evaluated the effect various electrical vagus nerve stimulation strategies have on glycemia and glucose-regulating hormones, as a first step to developing a novel therapy of type 2 diabetes. Sprague-Dawley rats were anesthetized, the abdominal (anterior) vagus nerve implanted, and various stimulation strategies applied to the nerve: (a) 15 Hz; (b) 4 kHz, or 40 kHz and; (c) a combination of 15 Hz and 40 kHz to directionally activate afferent or efferent vagal fibers. Following a glucose bolus (500 mg/kg, I.V.), stimulation strategies were applied (60 min) and serial blood samples taken. No stimulation was used as a crossover control sequence. Applying 15 Hz stimulation significantly increased glucose (+2.9 ± 0.2 mM·hr, p = .015) and glucagon (+17.1 ± 8.0 pg·hr/ml, p = .022), compared to no stimulation. Application of 4 kHz stimulation also significantly increased glucose levels (+1.5 ± 0.5 mM·hr, p = .049), while 40 kHz frequency stimulation resulted in no changes to glucose levels but did significantly lower glucagon (-12.3 ± 1.1 pg·hr/ml, p = .0009). Directional afferent stimulation increased glucose (+2.4 ± 1.5 mM·hr) and glucagon levels (+39.5 ± 15.0 pg·hr/ml). Despite hyperglycemia resulting when VNS, aVNS, and 4 kHz stimulation strategies were applied, the changes in insulin levels were not significant (p ≥ .05). In summary, vagus nerve stimulation modulates glycemia by effecting glucagon and insulin secretions, and high-frequency 40 kHz stimulation may have potential application for the treatment of type 2 diabetes.
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http://dx.doi.org/10.14814/phy2.14479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280012PMC
June 2020

Electrochemical and biological characterization of thin-film platinum-iridium alloy electrode coatings: a chronic in vivo study.

J Neural Eng 2020 06 22;17(3):036012. Epub 2020 Jun 22.

Bionics Institute, St. Vincent's Hospital, Melbourne, VIC, Australia.

Objective: To evaluate the electrochemical properties, biological response, and surface characterization of an electrodeposited Platinum-Iridium (Pt-Ir) electrode coating on cochlear implants subjected to chronic stimulation in vivo.

Approach: Electrochemical impedance spectroscopy (EIS), charge storage capacity (CSC), charge injection limit (CIL), and voltage transient (VT) impedance were measured bench-top before and after implant and in vivo. Coated Pt-Ir and uncoated Pt electrode arrays were implanted into cochlea of normal hearing rats and stimulated for ∼4 h d, 5 d week for 5 weeks at levels within the normal clinical range. Neural function was monitored using electrically-evoked auditory brainstem responses. After explant, the electrode surfaces were assessed, and cochleae examined histologically.

Main Results: When measured on bench-top before and after stimulation, Pt-Ir coated electrodes had significantly lower VT impedance (p < 0.001) and significantly higher CSC (p < 0.001) and CIL (p < 0.001) compared to uncoated Pt electrodes. In vivo, the CSC and CIL of Pt-Ir were significantly higher than Pt throughout the implantation period (p= 0.047 and p< 0.001, respectively); however, the VT impedance (p= 0.3) was not. There was no difference in foreign body response between material cohorts, although cochleae implanted with coated electrodes contained small deposits of Pt-Ir. There was no evidence of increased neural loss or loss of neural function in either group. Surface examination revealed no Pt corrosion on any electrodes.

Significance: Electrodeposited Pt-Ir electrodes demonstrated significant improvements in electrochemical performance on the bench-top and in vivo compared to uncoated Pt. Neural function and tissue response to Pt-Ir electrodes were not different from uncoated Pt, despite small deposits of Pt-Ir in the tissue capsule. Electrodeposited Pt-Ir coatings offer promise as an improved electrode coating for active neural prostheses.
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http://dx.doi.org/10.1088/1741-2552/ab933dDOI Listing
June 2020

Transmural impedance detects graded changes of inflammation in experimental colitis.

R Soc Open Sci 2020 Feb 19;7(2):191819. Epub 2020 Feb 19.

Bionics Institute, Fitzroy, Victoria 3065, Australia.

Ulcerative colitis is a chronic disease in which the mucosa of the colon or rectum becomes inflamed. An objective biomarker of inflammation will provide quantitative measures to support qualitative assessment during an endoscopic examination. Previous studies show that transmural electrical impedance is a quantifiable biomarker of inflammation. Here, we hypothesize that impedance detects spatially restricted areas of inflammation, thereby allowing the distinction between regions that differ in their severity of inflammation. A platinum ball electrode was placed into minimally inflamed (i.e. normal) or 2,4,6-trinitrobenzene sulphonic acid (TNBS)-inflamed colonic regions of rats and impedance measurements obtained by passing current between the intraluminal and subcutaneous return electrode. Histology of the colon was correlated with impedance measurements. The impedance of minimally inflamed (normal) tissue was 1.5-1.9 kΩ. Following TNBS injection, impedance significantly decreased within the inflammatory penumbra ( < 0.05), and decreased more in the inflammatory epicentre ( = 0.02). Histological damage correlated with impedance values ( < 0.05). Thus, impedance values of 1.5-1.9, 1.3-1.4 and 0.9-1.1 kΩ corresponded to minimally inflamed, mildly inflamed and moderately inflamed tissue, respectively. In conclusion, transmural impedance is an objective, spatially localized biomarker of mucosal integrity, and distinguishes between severities of intestinal inflammation.
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http://dx.doi.org/10.1098/rsos.191819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062110PMC
February 2020

Electrochemical and biological performance of chronically stimulated conductive hydrogel electrodes.

J Neural Eng 2020 04 9;17(2):026018. Epub 2020 Apr 9.

Bionics Institute, St. Vincent's Hospital, Melbourne, VIC, Australia.

Objective: Evaluate electrochemical properties, biological response, and surface characterization of a conductive hydrogel (CH) coating following chronic in vivo stimulation.

Approach: Coated CH or uncoated smooth platinum (Pt) electrode arrays were implanted into the cochlea of rats and stimulated over a 5 week period with more than 57 million biphasic current pulses. Electrochemical impedance spectroscopy (EIS), charge storage capacity (CSC), charge injection limit (CIL), and voltage transient (VT) impedance were measured on the bench before and after stimulation, and in vivo during the stimulation program. Electrically-evoked auditory brainstem responses were recorded to monitor neural function. Following explant, the cochleae were examined histologically and electrodes were examined using scanning electron microscopy.

Main Results: CH coated electrodes demonstrated a bench-top electrochemical advantage over Pt electrodes before and after the electrical stimulation program. In vivo, CH coated electrodes also had a significant advantage over Pt electrodes throughout the stimulation program, exhibiting higher CSC (p= 0.002), larger CIL (p = 0.002), and lower VT impedance (p < 0.001). The CH cohort exhibited a greater tissue response (p= 0.003) with small deposits of particulate material within the tissue capsule. There was no loss in auditory neuron density or change in neural response thresholds in any cochleae. Examination of the electrode surface revealed that most CH electrodes exhibited some coating loss; however, there was no evidence of corrosion in the underlying Pt.

Significance: CH coated electrodes demonstrated significant electrochemical advantages on the bench-top and in vivo and maintained neural function despite an increased tissue response and coating loss. While further research is required to understand the cause of the coating loss, CH electrodes provide promise for use in neural prostheses.
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http://dx.doi.org/10.1088/1741-2552/ab7cfcDOI Listing
April 2020

Slim electrodes for improved targeting in deep brain stimulation.

J Neural Eng 2020 03 26;17(2):026008. Epub 2020 Mar 26.

Bionics Institute, East Melbourne, Australia. Author to whom any correspondence should be addressed.

Objective: The efficacy of deep brain stimulation can be limited by factors including poor selectivity of stimulation, targeting error, and complications related to implant reliability and stability. We aimed to improve surgical outcomes by evaluating electrode leads with smaller diameter electrode and microelectrodes incorporated which can be used for assisting targeting.

Approach: Electrode arrays were constructed with two different diameters of 0.65 mm and the standard 1.3 mm. Micro-electrodes were incorporated into the slim electrode arrays for recording spiking neural activity. Arrays were bilaterally implanted into the medial geniculate body (MGB) in nine anaesthetised cats for 24-40 h using stereotactic techniques. Recordings of auditory evoked field potentials and multi-unit activity were obtained at 1 mm intervals along the electrode insertion track. Insertion trauma was evaluated histologically.

Main Results: Evoked auditory field potentials were recorded from ring and micro-electrodes in the vicinity of the medial geniculate body. Spiking activity was recorded from 81% of the microelectrodes approaching the MGB. Histological examination showed localized surgical trauma along the implant. The extent of haemorrhage surrounding the track was measured and found to be significantly reduced with the slim electrodes (541 ± 455 µm vs. 827 ± 647 µm; P < 0.001). Scoring of the trauma, focusing on tissue disruption, haemorrhage, oedema of glial parenchyma and pyknosis, revealed a significantly lower trauma score for the slim electrodes (P < 0.0001).

Significance: The slim electrodes reduced the extent of acute trauma, while still providing adequate electrode impedance for both stimulating and recording, and providing the option to target stimulate smaller volumes of tissue. The incorporation of microelectrodes into the electrode array may allow for a simplified, single-step surgical approach where confirmatory micro-targeting is done with the same lead used for permanent implantation.
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http://dx.doi.org/10.1088/1741-2552/ab7a51DOI Listing
March 2020

Combined optogenetic and electrical stimulation of auditory neurons increases effective stimulation frequency-an in vitro study.

J Neural Eng 2020 02 19;17(1):016069. Epub 2020 Feb 19.

ARC Training Centre in Biodevices, Swinburne University of Technology, Hawthorn, VIC 3122, Australia.

Objective: The performance of neuroprostheses, including cochlear and retinal implants, is currently constrained by the spatial resolution of electrical stimulation. Optogenetics has improved the spatial control of neurons in vivo but lacks the fast-temporal dynamics required for auditory and retinal signalling. The objective of this study is to demonstrate that combining optical and electrical stimulation in vitro could address some of the limitations associated with each of the stimulus modes when used independently.

Approach: The response of murine auditory neurons expressing ChR2-H134 to combined optical and electrical stimulation was characterised using whole cell patch clamp electrophysiology.

Main Results: Optogenetic costimulation produces a three-fold increase in peak firing rate compared to optical stimulation alone and allows spikes to be evoked by combined subthreshold optical and electrical inputs. Subthreshold optical depolarisation also facilitated spiking in auditory neurons for periods of up to 30 ms without evidence of wide-scale Na inactivation.

Significance: These findings may contribute to the development of spatially and temporally selective optogenetic-based neuroprosthetics and complement recent developments in 'fast opsins'.
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http://dx.doi.org/10.1088/1741-2552/ab6a68DOI Listing
February 2020

Electrochemical and mechanical performance of reduced graphene oxide, conductive hydrogel, and electrodeposited Pt-Ir coated electrodes: an active in vitro study.

J Neural Eng 2019 12 23;17(1):016015. Epub 2019 Dec 23.

Bionics Institute, St. Vincent's Hospital, Melbourne, VIC, Australia.

Objective: To systematically compare the in vitro electrochemical and mechanical properties of several electrode coatings that have been reported to increase the efficacy of medical bionics devices by increasing the amount of charge that can be delivered safely to the target neural tissue.

Approach: Smooth platinum (Pt) ring and disc electrodes were coated with reduced graphene oxide, conductive hydrogel, or electrodeposited Pt-Ir. Electrodes with coatings were compared with uncoated smooth Pt electrodes before and after an in vitro accelerated aging protocol. The various coatings were compared mechanically using the adhesion-by-tape test. Electrodes were stimulated in saline for 24 hours/day 7 days/week for 21 d at 85 °C (1.6-year equivalence) at a constant charge density of 200 µC/cm/phase. Electrodes were graded on surface corrosion and trace analysis of Pt in the electrolyte after aging. Electrochemical measurements performed before, during, and after aging included electrochemical impedance spectroscopy, cyclic voltammetry, and charge injection limit and impedance from voltage transient recordings.

Main Results: All three coatings adhered well to smooth Pt and exhibited electrochemical advantage over smooth Pt electrodes prior to aging. After aging, graphene coated electrodes displayed a stimulation-induced increase in impedance and reduction in the charge injection limit (p   <  0.001), alongside extensive corrosion and release of Pt into the electrolyte. In contrast, both conductive hydrogel and Pt-Ir coated electrodes had smaller impedances and larger charge injection limits than smooth Pt electrodes (p   <  0.001) following aging regardless of the stimulus level and with little evidence of corrosion or Pt dissolution.

Significance: This study rigorously tested the mechanical and electrochemical performance of electrode coatings in vitro and provided suitable candidates for future in vivo testing.
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http://dx.doi.org/10.1088/1741-2552/ab5163DOI Listing
December 2019

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

Hear Res 2019 09 21;380:137-149. Epub 2019 Jun 21.

Translational Neuroscience Facility & Department of Physiology, School of Medical Sciences, UNSW Sydney, NSW, Australia. Electronic address:

This Review outlines the development of DNA-based therapeutics for treatment of hearing loss, and in particular, considers the potential to utilize the properties of recombinant neurotrophins to improve cochlear auditory (spiral ganglion) neuron survival and repair. This potential to reduce spiral ganglion neuron death and indeed re-grow the auditory nerve fibres has been the subject of considerable pre-clinical evaluation over decades with the view of improving the neural interface with cochlear implants. This provides the context for discussion about the development of a novel means of using cochlear implant electrode arrays for gene electrotransfer. Mesenchymal cells which line the cochlear perilymphatic compartment can be selectively transfected with (naked) plasmid DNA using array - based gene electrotransfer, termed 'close-field electroporation'. This technology is able to drive expression of brain derived neurotrophic factor (BDNF) in the deafened guinea pig model, causing re-growth of the spiral ganglion peripheral neurites towards the mesenchymla cells, and hence into close proximity with cochlear implant electrodes within scala tympani. This was associated with functional enhancement of the cochlear implant neural interface (lower neural recruitment thresholds and expanded dynamic range, measured using electrically - evoked auditory brainstem responses). The basis for the efficiency of close-field electroporation arises from the compression of the electric field in proximity to the ganged cochlear implant electrodes. The regions close to the array with highest field strength corresponded closely to the distribution of bioreporter cells (adherent human embryonic kidney (HEK293)) expressing green fluorescent reporter protein (GFP) following gene electrotransfer. The optimization of the gene electrotransfer parameters using this cell-based model correlated closely with in vitro and in vivo cochlear gene delivery outcomes. The migration of the cochlear implant electrode array-based gene electrotransfer platform towards a clinical trial for neurotrophin-based enhancement of cochlear implants is supported by availability of a novel regulatory compliant mini-plasmid DNA backbone (pFAR4; plasmid Free of Antibiotic Resistance v.4) which could be used to package a 'humanized' neurotrophin expression cassette. A reporter cassette packaged into pFAR4 produced prominent GFP expression in the guinea pig basal turn perilymphatic scalae. More broadly, close-field gene electrotransfer may lend itself to a spectrum of potential DNA therapeutics applications benefitting from titratable, localised, delivery of naked DNA, for gene augmentation, targeted gene regulation, or gene substitution strategies.
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http://dx.doi.org/10.1016/j.heares.2019.06.002DOI Listing
September 2019

Deep brain stimulation for Parkinson's disease modulates high-frequency evoked and spontaneous neural activity.

Neurobiol Dis 2019 10 2;130:104522. Epub 2019 Jul 2.

Bionics Institute, Melbourne, Australia; Department of Neurology, The Royal Melbourne and Austin Hospitals, Melbourne, Australia; Department of Medicine, The University of Melbourne, Parkville, Australia.

Deep brain stimulation is an established therapy for Parkinson's disease; however, its effectiveness is hindered by limited understanding of therapeutic mechanisms and the lack of a robust feedback signal for tailoring stimulation. We recently reported that subthalamic nucleus deep brain stimulation evokes a neural response resembling a decaying high-frequency (200-500 Hz) oscillation that typically has a duration of at least 10 ms and is localizable to the dorsal sub-region. As the morphology of this response suggests a propensity for the underlying neural circuitry to oscillate at a particular frequency, we have named it evoked resonant neural activity. Here, we determine whether this evoked activity is modulated by therapeutic stimulation - a critical attribute of a feedback signal. Furthermore, we investigated whether any related changes occurred in spontaneous local field potentials. Evoked and spontaneous neural activity was intraoperatively recorded from 19 subthalamic nuclei in patients with Parkinson's disease. Recordings were obtained before therapeutic stimulation and during 130 Hz stimulation at increasing amplitudes (0.67-3.38 mA), 'washout' of therapeutic effects, and non-therapeutic 20 Hz stimulation. Therapeutic efficacy was assessed using clinical bradykinesia and rigidity scores. The frequency and amplitude of evoked resonant neural activity varied with the level of 130 Hz stimulation (p < .001). This modulation coincided with improvement in bradykinesia and rigidity (p < .001), and correlated with spontaneous beta band suppression (p < .001). Evoked neural activity occupied a similar frequency band to spontaneous high-frequency oscillations (200-400 Hz), both of which decreased to around twice the 130 Hz stimulation rate. Non-therapeutic stimulation at 20 Hz evoked, but did not modulate, resonant activity. These results indicate that therapeutic deep brain stimulation alters the frequency of evoked and spontaneous oscillations recorded in the subthalamic nucleus that are likely generated by loops within the cortico-basal ganglia-thalamo-cortical network. Evoked resonant neural activity therefore has potential as a tool for providing insight into brain network function and has key attributes of a dynamic feedback signal for optimizing therapy.
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http://dx.doi.org/10.1016/j.nbd.2019.104522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879321PMC
October 2019

Electrically conducting diamond films grown on platinum foil for neural stimulation.

J Neural Eng 2019 10 9;16(6):066002. Epub 2019 Oct 9.

Department of Medical Bionics, The University of Melbourne, Parkville, Melbourne VIC 3010, Australia. Department of Physics, Jahangirnagar University, Savar, Dhaka 1342, Bangladesh.

Objective: With the strong drive towards miniaturization of active implantable medical devices and the need to improve the resolution of neural stimulation arrays, there is keen interest in the manufacture of small electrodes capable of safe, continuous stimulation. Traditional materials such as platinum do not possess the necessary electrochemical properties to stimulate neurons safely when electrodes are very small (i.e. typically less than about 300 µm (78 400 µm)). While there are several commercially viable alternative electrode materials such as titanium nitride and iridium oxide, an attractive approach is modification of existing Pt arrays via a high electrochemical capacitance material coating. Such a composite electrode could still take advantage of the wide range of fabrication techniques used to make platinum-based devices. The coating, however, must be biocompatible, exhibit good adhesion and ideally be long lasting when implanted in the body.

Approach: Platinum foils were roughened to various degrees with regular arrays of laser milled pits. Conducting diamond films were grown on the foils by microwave plasma chemical vapor deposition. The adhesion strength of the films to the platinum was assessed by prolonged sonication and accelerated aging. Electrochemical properties were evaluated and compared to previous work.

Main Results: In line with previous results, diamond coatings increased the charge injection capacity of the platinum foil by more than 300% after functionalization within an oxygen plasma. Roughening of the underlying platinum substrate by laser milling was required to generate strong adhesion between the diamond and the Pt foil. Electrical stress testing, near the limits of safe operation, showed that the diamond films were more electrochemically stable than platinum controls.

Significance: The article describes a new method to protect platinum electrodes from degradation in vivo. A 300% increase in charge injection means that device designers can safely employ diamond coated platinum stimulation electrodes at much smaller sizes and greater density than is possible for platinum.
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http://dx.doi.org/10.1088/1741-2552/ab2e79DOI Listing
October 2019

Anti-inflammatory Effects of Abdominal Vagus Nerve Stimulation on Experimental Intestinal Inflammation.

Front Neurosci 2019 8;13:418. Epub 2019 May 8.

Bionics Institute, Fitzroy, VIC, Australia.

Electrical stimulation of the cervical vagus nerve is an emerging treatment for inflammatory bowel disease (IBD). However, side effects from cervical vagal nerve stimulation (VNS) are often reported by patients. Here we hypothesized that stimulating the vagus nerve closer to the end organ will have fewer off-target effects and will effectively reduce intestinal inflammation. Specifically, we aimed to: (i) compare off-target effects during abdominal and cervical VNS; (ii) verify that VNS levels were suprathreshold; and (iii) determine whether abdominal VNS reduces chemically-induced intestinal inflammation in rats. An electrode array was developed in-house to stimulate and record vagal neural responses. In a non-recovery experiment, stimulation-induced off-target effects were measured by implanting the cervical and abdominal vagus nerves of anaesthetized rats ( = 5) and recording changes to heart rate, respiration and blood pressure during stimulation (10 Hz; symmetric biphasic current pulse; 320 nC per phase). In a chronic experiment, the efficacy of VNS treatment was assessed by implanting an electrode array onto the abdominal vagus nerve and recording electrically-evoked neural responses during the implantation period. After 14 days, the intestine was inflamed with TNBS (2.5% 2,4,6-trinitrobenzene sulphonic acid) and rats received therapeutic VNS ( = 7; 10 Hz; 320 nC per phase; 3 h/day) or no stimulation ( = 8) for 4.5 days. Stool quality, plasma C-reactive protein and histology of the inflamed intestine were assessed. Data show that abdominal VNS had no effect (two-way RM-ANOVA: ≥ 0.05) on cardiac, respiratory and blood pressure parameters. However, during cervical VNS heart rate decreased by 31 ± 9 beats/minute ( ≥ 0.05), respiration was inhibited and blood pressure decreased. Data addressing efficacy of VNS treatment show that electrically-evoked neural response thresholds remained stable (one-way RM ANOVA: ≥ 0.05) and therapeutic stimulation remained above threshold. Chronically stimulated rats, compared to unstimulated rats, had improved stool quality (two-way RM ANOVA: < 0.0001), no blood in feces ( < 0.0001), reduced plasma C-reactive protein (two-way RM ANOVA: < 0.05) and a reduction in resident inflammatory cell populations within the intestine (Kruskal-Wallis: < 0.05). In conclusion, abdominal VNS did not evoke off-target effects, is an effective treatment of TNBS-induced inflammation, and may be an effective treatment of IBD in humans.
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http://dx.doi.org/10.3389/fnins.2019.00418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517481PMC
May 2019

Head and Gaze Behavior in Retinitis Pigmentosa.

Invest Ophthalmol Vis Sci 2019 05;60(6):2263-2273

The Bionics Institute of Australia, East Melbourne, Victoria, Australia.

Purpose: Peripheral visual field loss (PVFL) due to retinitis pigmentosa (RP) decreases saccades to areas of visual defect, leading to a habitually confined range of eye movement. We investigated the relative contributions of head and eye movement in RP patients and normal-sighted controls to determine whether this reduced eye movement is offset by increased head movement.

Methods: Eye-head coordination was examined in 18 early-moderate RP patients, 4 late-stage RP patients, and 19 normal-sighted controls. Three metrics were extracted: the extent of eye, head, and total gaze (eye+head) movement while viewing a naturalistic scene; head gain, the ratio of head movement to total gaze movement during smooth pursuit; and the customary oculomotor range (COMR), the orbital range within which the eye is preferentially maintained during a pro-saccade task.

Results: The late-stage RP group had minimal gaze movement and could not discern the naturalistic scene. Variance in head position in early-moderate RP was significantly greater than in controls, whereas variance in total gaze was similar. Head gain was greater in early-moderate RP than in controls, whereas COMR was smaller. Across groups, visual field extent was negatively correlated with head gain and positively correlated with COMR. Accounting for age effects, these results demonstrate increased head movement at the expense of eye movement in participants with PVFL.

Conclusions: RP is associated with an increased propensity for head movement during gaze shifts, and the magnitude of this effect is dependent on the severity of visual field loss.
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http://dx.doi.org/10.1167/iovs.18-26121DOI Listing
May 2019

Pharmacokinetics and tissue distribution of neurotrophin 3 after intracochlear delivery.

J Control Release 2019 04 18;299:53-63. Epub 2019 Feb 18.

Bionics Institute, Melbourne, Australia; University of Melbourne, Medical Bionics Department, Melbourne, Australia; University of Melbourne, Department of Otolaryngology, Melbourne, Australia.

Neurotrophin therapy has potential to reverse some forms of hearing loss. However, cochlear pharmacokinetic studies are challenging due to small fluid volumes. Here a radioactive tracer was used to determine neurotrophin-3 retention, distribution and clearance after intracochlear administration. I-neurotrophin-3 was injected into guinea pig cochleae using a sealed injection technique comparing dosing volumes, rates and concentrations up to 750 μg/mL. Retention was measured by whole-cochlear gamma counts at five time points while distribution and clearance were assessed by autoradiography. Smaller injection volumes and higher concentrations correlated with higher retention of neurotrophin-3. Distribution of neurotrophin-3 was widespread throughout the cochlear tissue, decreasing in concentration from base to apex. Tissue distribution was non-uniform, with greatest density in cells lining the scala tympani and lower density in neural target tissue. The time constant for clearance of neurotrophin-3 from cochlear tissues was 38 h but neurotrophin-3 remained detectable for at least 2 weeks. Neurotrophin-3 was evident in the semi-circular canals with minor spread to the contralateral cochlea. This study is the first comprehensive evaluation of the disposition profile for a protein therapy in the cochlea. The findings and methods in this study will provide valuable guidance for the development of protein therapies for hearing loss.
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http://dx.doi.org/10.1016/j.jconrel.2019.02.018DOI Listing
April 2019

Chronic intracochlear electrical stimulation at high charge densities results in platinum dissolution but not neural loss or functional changes in vivo.

J Neural Eng 2019 04 5;16(2):026009. Epub 2018 Dec 5.

Bionics Institute, St Vincent's Hospital, Melbourne, Australia. Medical Bionics Department, The University of Melbourne, Melbourne, Australia.

Objective: Although there are useful guidelines defining the boundary between damaging and non-damaging electrical stimulation they were derived from acute studies using large surface area electrodes in direct contact with cortical neurons. These parameters are a small subset of the parameters used by neural stimulators. More recently, histological examination of cochleae from patients that were long-term cochlear implant users have shown evidence of particulate platinum (Pt). The pathophysiological effect of Pt within the cochlea is unknown. We examined the response of the cochlea to stimulus levels beyond those regarded as safe, and to evaluate the pathophysiological response of the cochlea following chronic stimulation at charge densities designed to induce Pt corrosion in vivo.

Approach: 19 guinea pigs were systemically deafened and implanted with a cochlear electrode array containing eight Pt electrodes of 0.05, 0.075 or 0.2 mm area. Animals were electrically stimulated continuously for 28 d using charge balanced current pulses at charge densities of 400, 267 or 100 µC/cm/phase. Electrically-evoked auditory brainstem responses (EABRs) were recorded to monitor neural function. On completion of stimulation electrodes were examined using scanning electron microscopy (SEM) and cochleae examined histology. Finally, analysis of Pt was measured using energy dispersive x-ray spectroscopy (EDS) and inductively coupled plasma mass spectrometry (ICP-MS).

Main Results: Compared with unstimulated control electrodes and electrodes stimulated at 100 µC/cm/phase, stimulation at 267 or 400 µC/cm/phase resulted in significant Pt corrosion. Cochleae stimulated at these high charge densities contained particulate Pt. The extent of the foreign body response depended on the level of stimulation; cochleae stimulated at 267 or 400 µC/cm/phase exhibited an extensive tissue response that included a focal region of necrosis close to the electrode. Despite chronic stimulation at high charge densities there was no loss of auditory neurons (ANs) in stimulated cochleae compared with their contralateral controls. Indeed, we report a statistically significant increase in AN density proximal to electrodes stimulated at 267 or 400 µC/cm/phase. Finally, there was no evidence of a reduction in AN function associated with chronic stimulation at 100, 267 or 400 µC/cm/phase as evidenced by stable EABR thresholds over the stimulation program.

Significance: Chronic electrical stimulation of Pt electrodes at 267 or 400 µC/cm/phase evoked a vigorous tissue response and produced Pt corrosion products that were located close to the electrode. Despite these changes at the electrode/tissue interface there was no evidence of neural loss or a reduction in neural function.
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http://dx.doi.org/10.1088/1741-2552/aaf66bDOI Listing
April 2019

Electrical Field Shaping Techniques in a Feline Model of Retinal Degeneration.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:1222-1225

The majority of preclinical studies investigating multi-electrode field shaping stimulation strategies for retinal prostheses, have been conducted in normally-sighted animals. This study aimed to reassess the effectiveness of two electrical field shaping techniques that have been shown to work in healthy retinae, in a more clinically relevant animal model of photoreceptor degeneration. Four cats were unilaterally blinded via intravitreal injections of adenosine triphosphate. Cortical responses to traditional monopolar (MP) stimulation, focused multipolar (FMP) stimulation and two-dimensional current steering were recorded. Contrary to our previous work, we found no significant difference between the spread of cortical activation elicited by FMP and MP stimulation, and we were not able to reproduce cortical responses to singleelectrode retinal stimulation using two-dimensional current steering. These findings suggest that while shown to be effective in normally-sighted animals, these techniques may not be readily translatable to patients with retinal degeneration and require further optimization.
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http://dx.doi.org/10.1109/EMBC.2018.8512473DOI Listing
July 2018

Temporal Coding of Voice Pitch Contours in Mandarin Tones.

Front Neural Circuits 2018 24;12:55. Epub 2018 Jul 24.

Key Laboratory of Biorheological Science and Technology of Ministry of Education, Bioengineering College of Chongqing University, Chongqing, China.

Accurate perception of time-variant pitch is important for speech recognition, particularly for tonal languages with different lexical tones such as Mandarin, in which different tones convey different semantic information. Previous studies reported that the auditory nerve and cochlear nucleus can encode different pitches through phase-locked neural activities. However, little is known about how the inferior colliculus (IC) encodes the time-variant periodicity pitch of natural speech. In this study, the Mandarin syllable /ba/ pronounced with four lexical tones (flat, rising, falling then rising and falling) were used as stimuli. Local field potentials (LFPs) and single neuron activity were simultaneously recorded from 90 sites within contralateral IC of six urethane-anesthetized and decerebrate guinea pigs in response to the four stimuli. Analysis of the temporal information of LFPs showed that 93% of the LFPs exhibited robust encoding of periodicity pitch. Pitch strength of LFPs derived from the autocorrelogram was significantly ( < 0.001) stronger for rising tones than flat and falling tones. Pitch strength are also significantly increased ( < 0.05) with the characteristic frequency (CF). On the other hand, only 47% (42 or 90) of single neuron activities were significantly synchronized to the fundamental frequency of the stimulus suggesting that the temporal spiking pattern of single IC neuron could encode the time variant periodicity pitch of speech robustly. The difference between the number of LFPs and single neurons that encode the time-variant F0 voice pitch supports the notion of a transition at the level of IC from direct temporal coding in the spike trains of individual neurons to other form of neural representation.
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http://dx.doi.org/10.3389/fncir.2018.00055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066958PMC
March 2019

Subthalamic nucleus deep brain stimulation evokes resonant neural activity.

Ann Neurol 2018 05 4;83(5):1027-1031. Epub 2018 May 4.

Bionics Institute, East Melbourne, Victoria, Australia.

Deep brain stimulation (DBS) is a rapidly expanding treatment for neurological and psychiatric conditions; however, a target-specific biomarker is required to optimize therapy. Here, we show that DBS evokes a large-amplitude resonant neural response focally in the subthalamic nucleus. This response is greatest in the dorsal region (the clinically optimal stimulation target for Parkinson disease), coincides with improved clinical performance, is chronically recordable, and is present under general anesthesia. These features make it a readily utilizable electrophysiological signal that could potentially be used for guiding electrode implantation surgery and tailoring DBS therapy to improve patient outcomes. Ann Neurol 2018;83:1027-1031.
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http://dx.doi.org/10.1002/ana.25234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025792PMC
May 2018

An objective diagnostic method for inflammatory bowel disease.

R Soc Open Sci 2018 Mar 21;5(3):180107. Epub 2018 Mar 21.

Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, Victoria 3010, Australia.

Inflammatory damage to the bowel, as occurs in inflammatory bowel disease (IBD), is debilitating to patients. In both patients and animal experimental models, histological analyses of biopsies and endoscopic examinations are used to evaluate the disease state. However, such measurements often have delays and are invasive, while endoscopy is not quantitatively objective. Therefore, a real-time quantitative method to assess compromised mucosal barrier function is advantageous. We investigated the correlation of changes in electrical transmural impedance with histological measures of inflammation. Four platinum (Pt) ball electrodes were placed in the lumen of the rat small intestine, with a return electrode under the skin. Electrodes placed within the non-inflamed intestine generated stable impedances during the 3 h testing period. Following an intraluminal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), an established animal model of IBD, impedances in the inflamed region significantly decreased relative to a region not exposed to TNBS (< 0.05). Changes in intestinal transmural impedance were correlated (< 0.05) with histologically assessed damage to the mucosa and increases in neutrophil, eosinophil and T-cell populations at 3 h compared with tissue from control regions. This quantitative, real-time assay may have application in the diagnosis and clinical management of IBD.
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http://dx.doi.org/10.1098/rsos.180107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882753PMC
March 2018

Creating virtual electrodes with 2D current steering.

J Neural Eng 2018 06 23;15(3):035002. Epub 2018 Feb 23.

Bionics Institute, East Melbourne, VIC 3002, Australia. Department of Medical Bionics, The University of Melbourne, East Melbourne, VIC 3002, Australia.

Objective: Current steering techniques have shown promise in retinal prostheses as a way to increase the number of distinct percepts elicitable without increasing the number of implanted electrodes. Previously, it has been shown that 'virtual' electrodes can be created between simultaneously stimulated electrode pairs, producing unique cortical response patterns. This study investigated whether virtual electrodes could be created using 2D current steering, and whether these virtual electrodes can produce cortical responses with predictable spatial characteristics.

Approach: Normally-sighted eyes of seven adult anaesthetised cats were implanted with a 42-channel electrode array in the suprachoroidal space and multi-unit neural activity was recorded from the visual cortex. Stimuli were delivered to individual physical electrodes, or electrodes grouped into triangular, rectangular, and hexagonal arrangements. Varying proportions of charge were applied to each electrode in a group to 'steer' current and create virtual electrodes. The centroids of cortical responses to stimulation of virtual electrodes were compared to those evoked by stimulation of single physical electrodes.

Main Results: Responses to stimulation of groups of up to six electrodes with equal ratios of charge on each electrode resulted in cortical activation patterns that were similar to those elicited by the central physical electrode (centroids: RM ANOVA on ranks, p  >  0.05; neural spread: one-way ANOVA on Ranks, p  >  0.05). We were also able to steer the centroid of activation towards the direction of any of the electrodes of the group by applying a greater charge to that electrode, but the movement in the centroid was not found to be significant.

Significance: The results suggest that current steering is possible in two dimensions between up to at least six electrodes, indicating it may be possible to increase the number of percepts in patients without increasing the number of physical electrodes. Being able to reproduce spatial characteristics of responses to individual physical electrodes suggests that this technique could also be used to compensate for faulty electrodes.
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http://dx.doi.org/10.1088/1741-2552/aab1b8DOI Listing
June 2018

Gaze Compensation as a Technique for Improving Hand-Eye Coordination in Prosthetic Vision.

Transl Vis Sci Technol 2018 Jan 5;7(1). Epub 2018 Jan 5.

The Bionics Institute of Australia, East Melbourne, Australia.

Purpose: Shifting the region-of-interest within the input image to compensate for gaze shifts ("gaze compensation") may improve hand-eye coordination in visual prostheses that incorporate an external camera. The present study investigated the effects of eye movement on hand-eye coordination under simulated prosthetic vision (SPV), and measured the coordination benefits of gaze compensation.

Methods: Seven healthy-sighted subjects performed a target localization-pointing task under SPV. Three conditions were tested, modeling: retinally stabilized phosphenes (uncompensated); gaze compensation; and no phosphene movement (center-fixed). The error in pointing was quantified for each condition.

Results: Gaze compensation yielded a significantly smaller pointing error than the uncompensated condition for six of seven subjects, and a similar or smaller pointing error than the center-fixed condition for all subjects (two-way ANOVA, < 0.05). Pointing error eccentricity and gaze eccentricity were moderately correlated in the uncompensated condition (azimuth: = 0.47; elevation: = 0.51) but not in the gaze-compensated condition (azimuth: = 0.01; elevation: = 0.00). Increased variability in gaze at the time of pointing was correlated with greater reduction in pointing error in the center-fixed condition compared with the uncompensated condition ( = 0.64).

Conclusions: Eccentric eye position impedes hand-eye coordination in SPV. While limiting eye eccentricity in uncompensated viewing can reduce errors, gaze compensation is effective in improving coordination for subjects unable to maintain fixation.

Translational Relevance: The results highlight the present necessity for suppressing eye movement and support the use of gaze compensation to improve hand-eye coordination and localization performance in prosthetic vision.
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http://dx.doi.org/10.1167/tvst.7.1.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5759363PMC
January 2018
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