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Introduction: Current brain-based visual prostheses pose significant challenges impeding adoption such as the necessarily complex surgeries and occurrence of more substantial side effects due to the sensitivity of the brain. This has led to much effort toward vision restoration being focused on the more approachable part of the brain - the retina. Here we introduce a novel, parameterized simulation platform that enables study of human retinal degeneration and optimization of stimulation strategies. The platform bears immense potential for patient-specific tailoring and serves to enhance artificial vision solutions for individuals with visual impairments., Material and Method: Our virtual retina is developed using the software package, NEURON. This virtual retina platform supports large-scale simulations of over 10,000 neurons whilst upholding strong biological plausibility with multiple important visual pathways and detailed network properties. The comprehensive three-dimensional model includes photoreceptors, horizontal cells, bipolar cells, amacrine cells, and midget and parasol retinal ganglion cells, with comprehensive network connectivity across various eccentricities (1 mm to 5 mm from the fovea) in the human retina. The model is constructed using electrophysiology, immunohistology, and optical coherence tomography imaging data from healthy and degenerate human retinas. We validated our model by replicating numerous experimental observations from human and primate retina, with a particular focus on retinal degeneration., Result: We simulated interactions between diseased retinas and state-of-the-art retinal implants, shedding light on the limitations of commercial retinal prostheses. Our results suggested that appropriate stimulation settings with intraretinal prototype devices could leverage network-mediated activation to achieve activation mosaics more alike that of the retina's response to natural light, promoting the prospect of more naturalistic vision. Our study additionally highlights the importance of controlling inhibitory circuits in the retinal network to induce functionally relevant retinal activity., Conclusion: This study demonstrates the potential of this software package and highlights its utility as a valuable tool for engineers, scientists, and clinicians in the design and optimisation of retinal stimulation devices for both research and educational applications., Competing Interests: Declaration of Competing Interest ☒ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Keith Ly reports financial support was provided by Australian Government Research Training Program and HDR Completion Scholarships. Michael L. Italiano reports financial support was provided by Australian Government Research Training Program and HDR Completion Scholarships. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

Platinum (Pt) is the metal of choice for electrodes in implantable neural prostheses like the cochlear implants, deep brain stimulating devices, and brain-computer interfacing technologies. However, it is well known since the 1970s that Pt dissolution occurs with electrical stimulation. More recent clinical and in vivo studies have shown signs of corrosion in explanted electrode arrays and the presence of Pt-containing particulates in tissue samples. The process of degradation and release of metallic ions and particles can significantly impact on device performance. Moreover, the effects of Pt dissolution products on tissue health and function are still largely unknown. This is due to the highly complex chemistry underlying the dissolution process and the difficulty in decoupling electrical and chemical effects on biological responses. Understanding the mechanisms and effects of Pt dissolution proves challenging as the dissolution process can be influenced by electrical, chemical, physical, and biological factors, all of them highly variable between experimental settings. By evaluating comprehensive findings on Pt dissolution mechanisms reported in the fuel cell field, this review presents a critical analysis of the possible mechanisms that drive Pt dissolution in neural stimulation in vitro and in vivo. Stimulation parameters, such as aggregate charge, charge density, and electrochemical potential can all impact the levels of dissolved Pt. However, chemical factors such as electrolyte types, dissolved gases, and pH can all influence dissolution, confounding the findings of in vitro studies with multiple variables. Biological factors, such as proteins, have been documented to exhibit a mitigating effect on the dissolution process. Other biological factors like cells and fibro-proliferative responses, such as fibrosis and gliosis, impact on electrode properties and are suspected to impact on Pt dissolution. However, the relationship between electrical properties of stimulating electrodes and Pt dissolution remains contentious. Host responses to Pt degradation products are also controversial due to the unknown chemistry of Pt compounds formed and the lack of understanding of Pt distribution in clinical scenarios. The cytotoxicity of Pt produced via electrical stimulation appears similar to Pt-based compounds, including hexachloroplatinates and chemotherapeutic agents like cisplatin. While the levels of Pt produced under clinical and acute stimulation regimes were typically an order of magnitude lower than toxic concentrations observed in vitro, further research is needed to accurately assess the mass balance and type of Pt produced during long-term stimulation and its impact on tissue response. Finally, approaches to mitigating the dissolution process are reviewed. A wide variety of approaches, including stimulation strategies, coating electrode materials, and surface modification techniques to avoid excess charge during stimulation and minimise tissue response, may ultimately support long-term and safe operation of neural stimulating devices., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To achieve the accurate recognition of biomarkers or pathological characteristics within tissues or cells, in situ detection using biosensor technology offers crucial insights into the nature, stage, and progression of diseases, paving the way for enhanced precision in diagnostic approaches and treatment strategies. The implementation of needle-shaped biosensors (N-biosensors) presents a highly promising method for conducting in situ measurements of clinical biomarkers in various organs, such as in the brain or spinal cord. Previous studies have highlighted the excellent performance of different N-biosensor designs in detecting biomarkers from clinical samples in vitro. Recent preclinical in vivo studies have also shown significant progress in the clinical translation of N-biosensor technology for in situ biomarker detection, enabling highly accurate diagnoses for cancer, diabetes, and infectious diseases. This article begins with an overview of current state-of-the-art benchtop N-biosensor designs, discusses their preclinical applications for sensitive diagnoses, and concludes by exploring the challenges and potential avenues for next-generation N-biosensor technology.

Objective. Electrical neuromodulation is an established non-pharmacological treatment for chronic pain. However, existing devices using pulsatile stimulation typically inhibit pain pathways indirectly and are not suitable for all types of chronic pain. Direct current (DC) stimulation is a recently developed technology which affects small-diameter fibres more strongly than pulsatile stimulation. Since nociceptors are predominantly small-diameter A δ and C fibres, we investigated if this property could be applied to preferentially reduce nociceptive signalling. Approach. We applied a DC waveform to the sciatic nerve in rats of both sexes and recorded multi-unit spinal activity evoked at the hindpaw using various natural stimuli corresponding to different sensory modalities rather than broad-spectrum electrical stimulus. To determine if DC neuromodulation is effective across different types of chronic pain, tests were performed in models of neuropathic and inflammatory pain. Main results. We found that in both pain models tested, DC application reduced responses evoked by noxious stimuli, as well as tactile-evoked responses which we suggest may be involved in allodynia. Different spinal activity of different modalities were reduced in naïve animals compared to the pain models, indicating that physiological changes such as those mediated by disease states could play a larger role than previously thought in determining neuromodulation outcomes. Significance. Our findings support the continued development of DC neuromodulation as a method for reduction of nociceptive signalling, and suggests that it may be effective at treating a broader range of aberrant pain conditions than existing devices., (Creative Commons Attribution license.)

Objective. Current retinal prosthetics are limited in their ability to precisely control firing patterns of functionally distinct retinal ganglion cell (RGC) types. The aim of this study was to characterise RGC responses to continuous, kilohertz-frequency-varying stimulation to assess its utility in controlling RGC activity. Approach. We used in vitro patch-clamp experiments to assess electrically-evoked ON and OFF RGC responses to frequency-varying pulse train sequences. In each sequence, the stimulation amplitude was kept constant while the stimulation frequency (0.5-10 kHz) was changed every 40 ms, in either a linearly increasing, linearly decreasing or randomised manner. The stimulation amplitude across sequences was increased from 10 to 300 µ A. Main results. We found that continuous stimulation without rest periods caused complex and irreproducible stimulus-response relationships, primarily due to strong stimulus-induced response adaptation and influence of the preceding stimulus frequency on the response to a subsequent stimulus. In addition, ON and OFF populations showed different sensitivities to continuous, frequency-varying pulse trains, with OFF cells generally exhibiting more dependency on frequency changes within a sequence. Finally, the ability to maintain spiking behaviour to continuous stimulation in RGCs significantly reduced over longer stimulation durations irrespective of the frequency order. Significance. This study represents an important step in advancing and understanding the utility of continuous frequency modulation in controlling functionally distinct RGCs. Our results indicate that continuous, kHz-frequency-varying stimulation sequences provide very limited control of RGC firing patterns due to inter-dependency between adjacent frequencies and generally, different RGC types do not display different frequency preferences under such stimulation conditions. For future stimulation strategies using kHz frequencies, careful consideration must be given to design appropriate pauses in stimulation, stimulation frequency order and the length of continuous stimulation duration., (© 2024 IOP Publishing Ltd.)

Optimization of retinal prostheses requires preclinical animal models that mimic features of human retinal disease, have appropriate eye sizes to accommodate implantable arrays, and provide options for unilateral degeneration so as to enable a contralateral, within-animal control eye. In absence of a suitable non-human primate model and shortcomings of our previous feline model generated through intravitreal injections of Adenosine Triphosphate (ATP), we aimed in the present study to develop an ATP induced degeneration model in the rabbit. Six normally sighted Dutch rabbits were monocularly blinded with this technique. Subsequent retinal degeneration was assessed with optical coherence tomography, electroretinography, and histological assays. Overall, there was a 42% and 26% reduction in a-wave and oscillatory potential amplitudes in the electroretinograms respectively, along with a global decrease in retinal thickness, with increased variability. Qualitative inspection also revealed that there were variable levels of retinal degeneration and remodeling both within and between treated eyes, mimicking the disease heterogeneity observed in retinitis pigmentosa. These findings confirm that ATP can be utilized to unilaterally induce blinding in rabbits and, potentially present an ideal model for future cortical recording experiments aimed at optimizing vision restoration strategies.Clinical Relevance- A rapid, unilaterally induced model of retinal degeneration in an animal with low binocular overlap and large eyes will allow for clinically valid recordings of downstream cortical activity following retinal stimulation. Such a model would be highly beneficial for the optimization of clinically appropriate vision restoration approaches.

Photoreceptor loss and inner retinal network remodeling severely impacts the ability of retinal prosthetic devices to create artificial vision. We developed a computational model of a degenerating retina based on rodent data and tested its response to retinal electrical stimulation. This model includes detailed network connectivity and diverse neural intrinsic properties, capable of exploring how the degenerated retina influences the performance of electrical stimulation during the degeneration process. Our model suggests the possibility of quantitatively modulating retinal ON and OFF pathways between phase II and III of retinal degeneration without requiring any differences between ON and OFF RGC intrinsic cellular properties. The model also provided insights about how remodeling events influence stage-dependent differential electrical responses of ON and OFF pathways.Clinical Relevance-This data-driven model can guide future development of retinal prostheses and stimulation strategies that may benefit patients at different stages of retinal disease progression, particularly in the early and mid-stages, thus increasing their global acceptance.

Modulation of functionally distinct nerve fibers with bioelectronic devices provides a therapeutic opportunity for various diseases. In this study, we began by developing a computational model including four major subtypes of myelinated fibers and one unmyelinated fiber. Second, we used an intrafascicular electrode to perform kHz-frequency electric stimulation to preferentially modulate a population of fibers. Our model suggests that fiber physical properties and electrode-to-fascicle distance severely impacts stimulus-response relationships. Large diameter fibers (Aα- and Aβ-) were only minimally influenced by the fascicle size and electrode location, while smaller diameter fibers (Aδ-, B- and C-) indicated a stronger dependency.Clinical Relevance- Our findings support the possibility of selectively modulating functionally-distinct nerve fibers using electrical stimulation in a small, localized region. Our model provides an effective tool to design next-generation implantable devices and therapeutic stimulation strategies toward minimizing off-target effects.

Optimal stimulus parameters for epiretinal prostheses have been investigated by analyzing retinal ganglion cell (RGC) spiking responses to white-noise electrical stimulation, through a spike-triggered average (STA) analysis technique. However, it is currently unknown as to activation of which retinal cells contribute to features of the STA. We conducted whole-cell patch clamping recordings in ON and OFF RGCs in response to white-noise epiretinal electrical stimulation by using different inhibitors of synaptic transmission in a healthy retina. An mGluR6 agonist, L-AP4, was firstly used to selectively block the output of photoreceptors (PRs) to ON bipolar cells (BCs). We subsequently fully blocked all synaptic inputs to RGCs using a combination of pharmacological agents. Our data shows that PRs dominate the ability of ON RGCs to integrate electrical pulses and form a unique STA shape, while BCs do not contribute in any way. In addition, our results demonstrate that the ability of OFF RGCs to integrate pulses is consistently impaired after blocking the PR to ON BC pathway. We hypothesise that the mechanisms underlying this co-effect are related to the narrow field AII amacrine cells connecting ON and OFF pathways.Clinical Relevance-Recent retinal studies recorded mirror-inverted STAs in ON and OFF retinal pathways, thus raising the possibility of designing a stimulation approach that can differentially activate ON and OFF pathways with electrical stimulation. However, the detailed contribution of three major retinal cell layers in forming characteristic STAs is still unclear. It is of great clinical relevance to investigate the isolated contribution of PRs to the electrically driven STA since PRs progressively degenerate in the course of retinal disease.

Introduction: A hallmark of photoreceptor degenerations is progressive, aberrant remodeling of the surviving retinal neurons and glia following photoreceptor loss. The exact relationship between neurons and glia remodeling in this late stage of retinal degeneration, however, is unclear. This study assessed this by examining Müller cell dysfunction via glutamine synthetase immunoreactivity and its spatial association with retinal neuron subpopulations through various cell markers., Methods: Aged Rd1 mice retinae (P150 - P536, n = minimum 5 per age) and control heterozygous rd1 mice retinae (P536, n = 5) were isolated, fixed and cryosectioned. Fluorescent immunolabeling of glutamine synthetase was performed and retinal areas quantified as having low glutamine synthetase immunoreactivity if proportion of labeled pixels in an area was less than two standard deviations of the mean of the total retina. Other Müller cell markers such as Sox9 and Glial fibrillary acidic protein along with neuronal cell markers Calbindin, Calretinin, recoverin, Protein kinase C-α, Glutamic acid decarboxylase 67, and Islet-1 were then quantified within areas of low and normal synthetase immunoreactivity., Results: Glutamine synthetase immunoreactivity was lost as a function of age in the rd1 mouse retina (P150 - P536). Immunoreactivity of other Müller cell markers, however, were unaffected suggesting Müller cells were still present in these low glutamine synthetase immunoreactive regions. Glutamine synthetase immunoreactivity loss affected specific neuronal populations: Type 2, Type 8 cone, and rod bipolar cells, as well as AII amacrine cells based on reduced recoverin, protein kinase Ca and parvalbumin immunoreactivity, respectively. The number of cell nuclei within regions of low glutamine synthetase immunoreactivity was also reduced suggesting possible neuronal loss rather than reduced cell marker immunoreactivity., Conclusion: These findings further support a strong interplay between glia-neuronal alterations in late-stage degeneration and highlight a need for future studies and consideration in intervention development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Reynisson, Kalloniatis, Fletcher, Shivdasani and Nivison-Smith.)

Purpose: Accurate mapping of phosphene locations from visual prostheses is vital to encode spatial information. This process may involve the subject pointing to evoked phosphene locations with their finger. Here, we demonstrate phosphene mapping for a retinal implant using eye movements and compare it with retinotopic electrode positions and previous results using conventional finger-based mapping., Methods: Three suprachoroidal retinal implant recipients (NCT03406416) indicated the spatial position of phosphenes. Electrodes were stimulated individually, and the subjects moved their finger (finger based) or their eyes (gaze based) to the perceived phosphene location. The distortion of the measured phosphene locations from the expected locations (retinotopic electrode locations) was characterized with Procrustes analysis., Results: The finger-based phosphene locations were compressed spatially relative to the expected locations all three subjects, but preserved the general retinotopic arrangement (scale factors ranged from 0.37 to 0.83). In two subjects, the gaze-based phosphene locations were similar to the expected locations (scale factors of 0.72 and 0.99). For the third subject, there was no apparent relationship between gaze-based phosphene locations and electrode locations (scale factor of 0.07)., Conclusions: Gaze-based phosphene mapping was achievable in two of three tested retinal prosthesis subjects and their derived phosphene maps correlated well with the retinotopic electrode layout. A third subject could not produce a coherent gaze-based phosphene map, but this may have revealed that their phosphenes were indistinct spatially., Translational Relevance: Gaze-based phosphene mapping is a viable alternative to conventional finger-based mapping, but may not be suitable for all subjects.

Objective. A major reason for poor visual outcomes provided by existing retinal prostheses is the limited knowledge of the impact of photoreceptor loss on retinal remodelling and its subsequent impact on neural responses to electrical stimulation. Computational network models of the neural retina assist in the understanding of normal retinal function but can be also useful for investigating diseased retinal responses to electrical stimulation. Approach. We developed and validated a biophysically detailed discrete neuronal network model of the retina in the software package NEURON. The model includes rod and cone photoreceptors, ON and OFF bipolar cell pathways, amacrine and horizontal cells and finally, ON and OFF retinal ganglion cells with detailed network connectivity and neural intrinsic properties. By accurately controlling the network parameters, we simulated the impact of varying levels of degeneration on retinal electrical function. Main results. Our model was able to reproduce characteristic monophasic and biphasic oscillatory patterns seen in ON and OFF neurons during retinal degeneration (RD). Oscillatory activity occurred at 3 Hz with partial photoreceptor loss and at 6 Hz when all photoreceptor input to the retina was removed. Oscillations were found to gradually weaken, then disappear when synapses and gap junctions were destroyed in the inner retina. Without requiring any changes to intrinsic cellular properties of individual inner retinal neurons, our results suggest that changes in connectivity alone were sufficient to give rise to neural oscillations during photoreceptor degeneration, and significant network connectivity destruction in the inner retina terminated the oscillations. Significance. Our results provide a platform for further understanding physiological retinal changes with progressive photoreceptor and inner RD. Furthermore, our model can be used to guide future stimulation strategies for retinal prostheses to benefit patients at different stages of disease progression, particularly in the early and mid-stages of RD., (© 2022 IOP Publishing Ltd.)

Purpose: To report the long-term observations of the electrode-tissue interface and perceptual stability in humans after chronic stimulation with a 44-channel suprachoroidal retinal implant., Methods: Four subjects (S1-4) with end-stage retinitis pigmentosa received the implant unilaterally (NCT03406416). Electrode impedances, electrode-retina distance (measured using optical coherence tomography imaging), and perceptual thresholds were monitored up to 181 weeks after implantation as the subjects used the prosthesis in the laboratory and in daily life. Stimulation charge density was limited to 32 µC/cm2 per phase., Results: Electrode impedances were stable longitudinally. The electrode-retina distances increased after surgery and then stabilized, and were well-described by an asymptotic exponential model. The stabilization of electrode-retina distances was variable between subjects, stabilizing after 45 weeks for S1, 63 weeks for S2, and 24 weeks for S3 (linear regression; Pgradient > 0.05). For S4, a statistically significant increase in electrode-retina distance persisted (P < 0.05), but by the study end point the rate of increase was clinically insignificant (exponential model: 0.33 µm/wk). Perceptual electrical thresholds were stable in one subject, decreased over time in two subjects (linear model; P < 0.05), and increased slightly in one subject but remained within the predefined charge limits (P = 0.02)., Conclusions: Chronic stimulation with the suprachoroidal retinal prosthesis over 3 years resulted in stable impedances, small individual changes in perceptual electrical thresholds, and no clinically significant increase in electrode-retina distances after a period of settling after surgery., Translational Relevance: Chronic stimulation with the 44-channel suprachoroidal retinal implant with a charge density of up to 32 µC/cm2 per phase is suitable for long-term use in humans.

Objective . Visual outcomes provided by present retinal prostheses that primarily target retinal ganglion cells (RGCs) through epiretinal stimulation remain rudimentary, partly due to the limited knowledge of retinal responses under electrical stimulation. Better understanding of how different retinal regions can be quantitatively controlled with high spatial accuracy, will be beneficial to the design of micro-electrode arrays and stimulation strategies for next-generation wide-view, high-resolution epiretinal implants. Approach . A computational model was developed to assess neural activity at different eccentricities (2 mm and 5 mm) within the human retina. This model included midget and parasol RGCs with anatomically accurate cell distribution and cell-specific morphological information. We then performed in silico investigations of region-specific RGC responses to epiretinal electrical stimulation using varied electrode sizes (5-210 µ m diameter), emulating both commercialized retinal implants and recently developed prototype devices. Main results . Our model of epiretinal stimulation predicted RGC population excitation analogous to the complex percepts reported in human subjects. Following this, our simulations suggest that midget and parasol RGCs have characteristic regional differences in excitation under preferred electrode sizes. Relatively central (2 mm) regions demonstrated higher number of excited RGCs but lower overall activated receptive field (RF) areas under the same stimulus amplitudes (two-way analysis of variance (ANOVA), p < 0.05). Furthermore, the activated RGC numbers per unit active RF area (number-RF ratio) were significantly higher in central than in peripheral regions, and higher in the midget than in the parasol population under all tested electrode sizes (two-way ANOVA, p < 0.05). Our simulations also suggested that smaller electrodes exhibit a higher range of controllable stimulation parameters to achieve pre-defined performance of RGC excitation. An empirical model: I = a · exp ( b · D ) + c of the stimulus amplitude ( I )-electrode diameter ( D ) relationship was constructed to achieve the pre-defined objective function values in different retinal regions, indicating the ability of controlling retinal outputs by fine-tuning the stimulation amplitude with different electrode sizes. Finally, our multielectrode simulations predicted differential neural crosstalk between adjacent electrodes in central temporal and peripheral temporal regions, providing insights towards establishing a non-uniformly distributed multielectrode array geometry for wide-view retinal implants. Significance. Stimulus-response properties in central and peripheral retina can provide useful information to estimate electrode parameters for region-specific activation by retinal stimulation. Our findings support the possibility of improving the performance of epiretinal prostheses by exploring the influence of electrode array geometry on activation of different retinal regions., (© 2022 IOP Publishing Ltd.)

Purpose: Artificial intelligence (AI) techniques are increasingly being used to classify retinal diseases. In this study we investigated the ability of a convolutional neural network (CNN) in categorizing histological images into different classes of retinal degeneration., Methods: Images were obtained from a chemically induced feline model of monocular retinal dystrophy and split into training and testing sets. The training set was graded for the level of retinal degeneration and used to train various CNN architectures. The testing set was evaluated through the best architecture and graded by six observers. Comparisons between model and observer classifications, and interobserver variability were measured. Finally, the effects of using less training images or images containing half the presentable context were investigated., Results: The best model gave weighted-F1 scores in the range 85% to 90%. Cohen kappa scores reached up to 0.86, indicating high agreement between the model and observers. Interobserver variability was consistent with the model-observer variability in the model's ability to match predictions with the observers. Image context restriction resulted in model performance reduction by up to 6% and at least one training set size resulted in a model performance reduction of 10% compared to the original size., Conclusions: Detecting the presence and severity of up to three classes of retinal degeneration in histological data can be reliably achieved with a deep learning classifier., Translational Relevance: This work lays the foundations for future AI models which could aid in the evaluation of more intricate changes occurring in retinal degeneration, particularly in other types of clinically derived image data.

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., Competing Interests: Disclosure: S.A. Titchener, Bionic Vision Technologies Pty Ltd (F); J. Kvansakul, Bionic Vision Technologies Pty Ltd (F); M.N. Shivdasani (P); J.B. Fallon, None; D.A.X. Nayagam, Bionic Vision Technologies Pty Ltd (F, P); S.B. Epp, Bionic Vision Technologies Pty Ltd (F); C.E. Williams, Bionic Vision Technologies Pty Ltd (F, P); N. Barnes, Bionic Vision Technologies Pty Ltd (F); W.G. Kentler, None; M. Kolic, Bionic Vision Technologies Pty Ltd (F); E.K. Baglin, Bionic Vision Technologies Pty Ltd (F); L.N. Ayton, None; C.J. Abbott, Bionic Vision Technologies Pty Ltd (F); C.D. Luu, Bionic Vision Technologies Pty Ltd (F, P); P.J. Allen, Bionic Vision Technologies Pty Ltd (F, P); M.A. Petoe, Bionic Vision Technologies Pty Ltd (F, P), (Copyright 2020 The Authors.)

Objective. The spatial resolution of an implantable neural stimulator can be improved by creation of virtual channels (VCs). VCs are commonly achieved through synchronized stimulation of multiple electrodes. It remains unknown whether asynchronous stimulation is able to generate comparable VC performance in retinal stimulation, and how VC can be optimized by re-designing stimulation settings. This study begins with exploring the feasibility of creating VCs using synchronous and asynchronous epiretinal stimulation, and ending with predicting the possible VC performance with a thorough exploration of stimulation parameter space. Approach. A computational model of epiretinal dual-electrode stimulation is developed to simulate the neural activity of a population of retinal ganglion cells (RGCs) under both synchronous and asynchronous stimulation conditions. The interaction between the electrode and RGCs under a range of stimulation parameters are simulated. Main results. Our simulation based on direct RGC activation suggests that VCs can be created using asynchronous stimulation. Two VC performance measures: 1) linearity in the change in centroid location of activated RGC populations, and 2) consistency in the size of activated RGC populations, have comparable performance under asynchronous and synchronous stimulation with appropriately selected stimulation parameters. Significance. Our findings support the possibility of creating VCs by directly activating RGCs under synchronous and asynchronous stimulation conditions. This study establishes the fundamental capability of VC creation based on temporal interactions within the RGC population alone and does not include the effects of potential indirect activation of any surviving inner retinal network neurons. Our results provide theoretical evidence for designing next-generation retinal prosthesis with higher spatial resolution., (© 2020 IOP Publishing Ltd.)

Objective: Due to their increased proximity to retinal ganglion cells (RGCs), epiretinal visual prostheses present the opportunity for eliciting phosphenes with low thresholds through direct RGC activation. This study characterised the in vivo performance of a novel prototype monolithic epiretinal prosthesis, containing Nitrogen incorporated ultrananocrystalline (N-UNCD) diamond electrodes., Approach: A prototype implant containing up to twenty-five 120 × 120 µm N-UNCD electrodes was implanted into 16 anaesthetised cats and attached to the retina either using a single tack or via magnetic coupling with a suprachoroidally placed magnet. Multiunit responses to retinal stimulation using charge-balanced biphasic current pulses were recorded acutely in the visual cortex using a multichannel planar array. Several stimulus parameters were varied including; the stimulating electrode, stimulus polarity, phase duration, return configuration and the number of electrodes stimulated simultaneously., Main Results: The rigid nature of the device and its form factor necessitated complex surgical procedures. Surgeries were considered successful in 10/16 animals and cortical responses to single electrode stimulation obtained in eight animals. Clinical imaging and histological outcomes showed severe retinal trauma caused by the device in situ in many instances. Cortical measures were found to significantly depend on the surgical outcomes of individual experiments, phase duration, return configuration and the number of electrodes stimulated simultaneously, but not stimulus polarity. Cortical thresholds were also found to increase over time within an experiment., Significance: The study successfully demonstrated that an epiretinal prosthesis containing diamond electrodes could produce cortical activity with high precision, albeit only in a small number of cases. Both surgical approaches were highly challenging in terms of reliable and consistent attachment to and stabilisation against the retina, and often resulted in severe retinal trauma. There are key challenges (device form factor and attachment technique) to be resolved for such a device to progress towards clinical application, as current surgical techniques are unable to address these issues.

Objective: This study focused on characterising the response of four major functionally-different retinal ganglion cells (RGCs) to a high frequency stimulus (HFS) paradigm., Approach: We used in vitro patch clamp experiments to assess the viability of evoking a differential response between different RGC types-OFF-Sustained, OFF-Transient, ON-Sustained and ON-Transient-under a wide range of HFS and stimulation amplitude combinations., Main Results: Of the four types, we found that the OFF-Sustained, OFF-Transient and ON-Transient RGCs could be differentially activated at various frequency and amplitude combinations, in particular, OFF-Sustained cells can be differentially targeted between 20-100 µA at all frequencies, OFF-Transient cells between 150-240 µA at 1 kHz and ON-Transient between 180-240 µA and 4-6 kHz. We further found that this differential activation held true when the stimulus duration was reduced from 300 ms to 50 ms. Finally, we found that the cell spiking response was not primarily dependent on total charge contained in the pulse train or current amplitude alone, but a combination of amplitude and frequency., Significance: These results indicate that HFS may be a promising method to target functionally-distinct neural pathways in the retina in an effort to improve the vision quality with retinal prostheses.

Present retinal neuroprostheses have limited performance capabilities due to indiscriminate activation of different neural pathways. Based on our success in differentially activating ON and OFF cells using high frequency stimuli in a healthy retina, in this study we explored whether we could achieve similar differential activation between these two cell types but in degenerate retina. We found that after blocking the synaptic network, ON retinal ganglion cells (RGCs) could be differentially activated at higher frequencies (4 - 6 kHz) and amplitudes (200 - 240 µA), and OFF RGCs at relatively lower amplitudes (80 - 160 µA) across all tested frequencies. We further found that both cell types could be controlled by quickly modulating the frequency using short stimulation bursts. This work takes us one step closer to reducing the likelihood of indiscriminate activation of RGCs by accurately controlling the activation of functionally-distinct neural pathways.

Cervical vagus nerve stimulation (VNS) is a neuromodulation therapy used in the treatment of several chronic disorders. In order to maximize the therapeutic effectiveness of VNS, it has become increasingly important to deliver fiber-specific neurostimulation, so that undesired effects can be minimized. Assessing the activation of different vagal fiber types through electrical stimulation is therefore essential for developing fiber-selective VNS therapies. Towards this goal, we conducted in silico investigations using a generic model of functionally distinct nerve fibers and clinically relevant cuff electrodes using COMSOL. Our model is constrained by histological observations from rat cervical vagus nerves and its outputs are validated against averaged compound nerve action potentials (CNAPs) obtained from rat vagus nerve recordings. We propose this model as an effective tool to design fiber-specific stimulation protocols before testing them in experimental animals.

The temporal pattern of action potentials can convey rich information in a variety of sensory systems. We describe a new non-invasive technique that enables precise, reliable generation of action potential patterns in tactile peripheral afferent neurons by brief taps on the skin. Using this technique, we demonstrate sophisticated coding of temporal information in the somatosensory system, that shows that perceived vibration frequency is not encoded in peripheral afferents as was expected by either their firing rate or the underlying periodicity of the stimulus. Instead, a burst gap or silent gap between trains of action potentials conveys frequency information. This opens the possibility of new encoding strategies that could be deployed to convey sensory information using mechanical or electrical stimulation in neural prostheses and brain-machine interfaces, and may extend to senses beyond artificial encoding of aspects of touch. We argue that a focus on appropriate use of effective temporal coding offers more prospects for rapid improvement in the function of these interfaces than attempts to scale-up existing devices., (Copyright © 2020 Vickery, Ng, Potas, Shivdasani, McIntyre, Nagi and Birznieks.)

This study assessed the developmental profile of unisensory and multisensory processes, and their contribution to children's intellectual abilities (8- and 11-year olds, N = 38, compared to adults, N = 19) using a simple audiovisual detection task and three incidental associative learning tasks with different sensory signals: visual-verbal with pseudowords, novel audiovisual, and visual-visual. The level of immaturity throughout childhood was dependent on both, the sensory signal type and the task. Associative learning was significantly enhanced with verbal sounds, compared to novel audiovisual and unisensory visual learning. Visual-verbal learning was also the best predictor of children's general intellectual abilities. The results demonstrate a separate developmental trajectory for visual and verbal multisensory processes and independent contributions to the development of cognitive abilities throughout childhood., (© 2019 Society for Research in Child Development.)