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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.

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.

An electrode array implanted into the optic nerve of rabbits selectively activates discrete regions of the primary visual cortex.

Although it is well known that attention can modulate multisensory processes in adults and infants, this relationship has not been investigated in school-age children. Attention abilities of 53 children (ages 7–13 years) were assessed using three subscales of the Test of Everyday Attention for Children (TEA-Ch): visuospatial attention (Sky Search [SS]), auditory sustained attention (Score), and audiovisual dual task (SSDT, where the SS and Score tasks are performed simultaneously). Multisensory processes were assessed using the McGurk effect (a verbal illusion where speech perception is altered by vision) and the Stream–Bounce (SB) effect (a nonverbal illusion where visual perception is altered by sound). The likelihood of perceiving both multisensory illusions tended to increase with age. The McGurk effect was significantly more pronounced in children who scored high on the audiovisual dual attention index (SSDT). In contrast, the SB effect was more pronounced in children with higher sustained auditory attention abilities as assessed by the Score index. These relationships between attention and the multisensory illusory percepts could not be explained solely by age or children’s intellectual abilities. This study suggests that the interplay between attention and multisensory processing depends on both the nature of the multisensory task and the type of attention needed to effectively merge information across the senses.

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.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.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; Pgradient0.05). For S4, a statistically significant increase in electrode-retina distance persisted (P0.05), 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; P0.05), and increased slightly in one subject but remained within the predefined charge limits (P = 0.02).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.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.

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.

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 µm 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.

Improvements to the efficacy of retinal neuroprostheses can be achieved by developing more sophisticated neural stimulation strategies to enable selective or differential activation of specific retinal ganglion cells (RGCs). Recent retinal studies have demonstrated the ability to differentially recruit ON and OFF RGCs – the two major information pathways of the retina – using high-frequency electrical stimulation (HFS). However, there remain many unknowns, since this is a relatively unexplored field. For example, can we achieve ON/OFF selectivity over a wide range of stimulus frequencies and amplitudes? Furthermore, existing demonstrations of HFS efficacy in retinal prostheses have been based on epiretinal placement of electrodes. Other clinically popular techniques include subretinal or suprachoroidal placement, where electrodes are located at the photoreceptor layer or in the suprachoroidal space, respectively, and these locations are quite distant from the RGC layer. Would HFS-based differential activation work from these locations? In this chapter, we conducted in silico investigations to explore the generalizability of HFS to differentially active ON and OFF RGCs. Computational models are particularly well suited for these investigations. The electric field can be accurately described by mathematical formulations, and simulated neurons can be “probed” at resolutions well beyond those achievable by today’s state-of-the-art experimental techniques.

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.

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. Funding Agencies|NHMRCNational Health and Medical Research Council of Australia [APP1028284]; ARCAustralian Research Council [DP200100630]; Australian Government Research Training Program ScholarshipAustralian GovernmentDepartment of Industry, Innovation and Science

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.

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 µm2)). 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.

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.

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.

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.

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.

In multichannel cochlear implants (CIs), current is delivered to specific electrodes along the cochlea in the form of amplitude-modulated pulse trains, to convey temporal and spectral cues. Our previous studies have shown that focused multipolar (FMP) and tripolar (TP) stimulation produce more restricted neural activation and reduced channel interactions in the inferior colliculus (IC) compared with traditional monopolar (MP) stimulation, suggesting that focusing of stimulation could produce better transmission of spectral information. The present study explored the capability of IC neurons to detect modulated CI stimulation with FMP and TP stimulation compared with MP stimulation. The study examined multiunit responses of IC neurons in acutely deafened guinea pigs by systematically varying the stimulation configuration, modulation depth, and stimulation level. Stimuli were sinusoidal amplitude-modulated pulse trains (carrier rate of 120 pulses/s). Modulation sensitivity was quantified by measuring modulation detection thresholds (MDTs), defined as the lowest modulation depth required to differentiate the response of a modulated stimulus from an unmodulated one. Whereas MP stimulation showed significantly lower MDTs than FMP and TP stimulation ( P values

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.

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.

There is an urgent need for conductive neural interfacing materials that exhibit mechanically compliant properties, while also retaining high strength and durability under physiological conditions. Currently, implantable electrode systems designed to stimulate and record neural activity are composed of rigid materials such as crystalline silicon and noble metals. While these materials are strong and chemically stable, their intrinsic stiffness and density induce glial scarring and eventual loss of electrode function in vivo. Conductive composites, such as polymers and hydrogels, have excellent electrochemical and mechanical properties, but are electrodeposited onto rigid and dense metallic substrates. In the work described here, strong and conductive microfibers (40-50 μm diameter) wet-spun from liquid crystalline dispersions of graphene oxide are fabricated into freestanding neural stimulation electrodes. The fibers are insulated with parylene-C and laser-treated, forming "brush" electrodes with diameters over 3.5 times that of the fiber shank. The fabrication method is fast, repeatable, and scalable for high-density 3D array structures and does not require additional welding or attachment of larger electrodes to wires. The electrodes are characterized electrochemically and used to stimulate live retina in vitro. Additionally, the electrodes are coated in a water-soluble sugar microneedle for implantation into, and subsequent recording from, visual cortex.

PURPOSE: Retinal prostheses use spatiotemporal patterns of electrical stimulation across multiple electrodes to provide visual percepts to blind patients. It is generally assumed that percepts produced by individual electrodes are independent of one another, which may not be the case. In this study, we aimed to quantify interactions between pairs of electrical stimuli delivered to the retina. METHODS: Normally sighted cats were implanted with a suprachoroidal electrode array. The retina was stimulated with a paired-pulse paradigm that consisted of a conditioning stimulus followed by a test stimulus, while recording multiunit activity in the visual cortex. Conditioning current, and spatial and temporal separation between the conditioning and test stimuli were varied. Cortical interactions were quantified by changes in multiunit activity elicited by stimulation with the paired-pulse paradigm, compared to stimulation of the test stimulus alone (control). RESULTS: Interactions varied as a function of conditioning current and temporal separation between the two stimulating pulses. Cortical activity increased compared to the control condition at an interstimulus delay of 1.025 ms and was significantly suppressed for delays between 20 and 90 ms, returning to near control levels for longer delays. The level of interactions increased when the conditioning current was increased. Interactions were found to be similar for electrode separations up to 3 mm. CONCLUSIONS: Interactions between sequential stimulation of pairs of electrodes in a suprachoroidal retinal prosthesis occur for delays up to 100 ms and electrode separations of several millimeters. Knowledge of these spatiotemporal interactions is essential for developing effective patterns of stimulation for retinal prostheses.

Background A key requirement for retinal prostheses is the ability for safe removal or replacement. We examined whether suprachoroidal electrode arrays can be removed or replaced after implantation. Methods Suprachoroidal electrode arrays were unilaterally implanted into 13 adult felines. After 1 month, arrays were surgically explanted (n = 6), replaced (n = 5) or undisturbed (n = 2). The retina was assessed periodically using fundus photography and optical coherence tomography. Three months after the initial implantation, the function of replaced or undisturbed arrays was assessed by measuring the responses of the visual cortex to retinal electrical stimulation. The histopathology of tissues surrounding the implant was examined. Results Array explantation or replacement was successful in all cases. Fundus photography showed localized disruption to the tapetum lucidum near the implant's tip in seven subjects following implantation. Although optical coherence tomography showed localized retinal changes, there were no widespread statistically significant differences in the thickness of the retinal layers or choroid. The distance between the electrodes and retina increased after device replacement but returned to control values within eight weeks (P

Wireless power and data transfer to medical implants is a research area where improvements in current state-of-the-art technologies are needed owing to the continuing efforts for miniaturization. At present, lithographical patterning of evaporated metals is widely used for miniature coil fabrication. This method produces coils that are limited to low micron or nanometer thicknesses leading to high impedance values and thus limiting their potential quality. In the present work we describe a novel technique, whereby trenches were milled into a diamond substrate and filled with silver active braze alloy, enabling the manufacture of small, high cross-section, low impedance microcoils capable of transferring up to 10 mW of power up to a distance of 6 mm. As a substitute for a metallic braze line used for hermetic sealing, a continuous metal loop when placed parallel and close to the coil surface reduced power transfer efficiency by 43%, but not significantly, when placed perpendicular to the microcoil surface. Encapsulation of the coil by growth of a further layer of diamond reduced the quality factor by an average of 38%, which can be largely avoided by prior oxygen plasma treatment. Furthermore, an accelerated ageing test after encapsulation showed that these coils are long lasting. Our results thus collectively highlight the feasibility of fabricating a high-cross section, biocompatible and long lasting miniaturized microcoil that could be used in either a neural recording or neuromuscular stimulation device.

Purpose: Simultaneous stimulation of multiple retinal electrodes in normally sighted animals shows promise in improving the resolution of retinal prostheses. However, the effects of simultaneous stimulation on degenerate retinae remain unknown. Therefore, we investigated the characteristics of cortical responses to multielectrode stimulation of the degenerate retina. Methods: Four adult cats were bilaterally implanted with retinal electrode arrays in the suprachoroidal space after unilateral adenosine triphosphate (ATP)-induced retinal photoreceptor degeneration. Functional and structural changes were characterized by using electroretinogram a-wave amplitude and optical coherence tomography. Multiunit activity was recorded from both hemispheres of the visual cortex. Responses to single- and multielectrode stimulation of the ATP-injected and fellow control eyes were characterized and compared. Results: The retinae of ATP-injected eyes displayed structural and functional changes consistent with mid- to late-stage photoreceptor degeneration and remodeling. Responses to multielectrode stimulation of the ATP-injected eyes exhibited shortened latencies, lower saturated spike counts, and higher thresholds, compared to stimulation of the fellow control eyes. Electrical receptive field sizes were significantly larger in the ATP-injected eye than in the control eye, and positively correlated with the extent of degeneration. Conclusions: Significant differences exist between cortical responses to stimulation of healthy and degenerate retinae. Our results highlight the importance of using a retinal degeneration model when evaluating the efficacy of novel stimulation paradigms.

Purpose With a retinal prosthesis connected to a head-mounted camera, subjects can perform low vision tasks using a combination of electrode discrimination and head-directed localization. The objective of the present study was to investigate the contribution of retinotopic electrode discrimination (perception corresponding to the arrangement of the implanted electrodes with respect to their position beneath the retina) to visual performance for three recipients of a 24-channel suprachoroidal retinal implant. Proficiency in retinotopic discrimination may allow good performance with smaller head movements, and identification of this ability would be useful for targeted rehabilitation. Methods Three participants with retinitis pigmentosa performed localization and grating acuity assessments using a suprachoroidal retinal prosthesis. We compared retinotopic and nonretinotopic electrode mapping and hypothesized that participants with measurable acuity in a normal retinotopic condition would be negatively impacted by the nonretinotopic condition. We also expected that participants without measurable acuity would preferentially use head movement over retinotopic information. Results Only one participant was able to complete the grating acuity task. In the localization task, this participant exhibited significantly greater head movements and significantly lower localization scores when using the nonretinotopic electrode mapping. There was no significant difference in localization performance or head movement for the remaining two subjects when comparing retinotopic to nonretinotopic electrode mapping. Conclusions Successful discrimination of retinotopic information is possible with a suprachoroidal retinal prosthesis. Head movement behavior during a localization task can be modified using a nonretinotopic mapping. Behavioral comparisons using retinotopic and nonretinotopic electrode mapping may be able to highlight deficiencies in retinotopic discrimination, with a view to address these deficiencies in a rehabilitation environment. (ClinicalTrials.gov number, NCT01603576).

The interface between medical implants and the human nervous system is rapidly becoming more and more complex. This rise in complexity is driving the need for increasing numbers of densely packed electrical feedthrough to carry signals to and from implanted devices. This is particularly crucial in the field of neural prosthesis where high resolution stimulating or recording arrays near peripheral nerves or in the brain could dramatically improve the performance of these devices. Here we describe a flexible strategy for implementing high density, high count arrays of hermetic electrical feedthroughs by forming conducting nitrogen doped nanocrystalline diamond channels within an insulating polycrystalline diamond substrate. A unique feature of these arrays is that the feedthroughs can themselves be used as stimulating electrodes for neural tissue. Our particular application is such a feedthrough, designed as a component of a retinal implant to restore vision to the blind. The hermeticity of the feedthroughs means that the array can also form part of an implantable capsule which can interface directly with internal electronic chips. The hermeticity of the array is demonstrated by helium leak tests and electrical and electrochemical characterisation of the feedthroughs is described. The nitrogen doped nanocrystalline diamond forming the electrical feedthroughs is shown to be non-cyctotoxic. New fabrication strategies, such as the one described here, combined with the exceptional biostability of diamond can be exploited to generate a range of biomedical implants that last for the lifetime of the user without fear of degradation.

Objective Simultaneous electrical stimulation of multiple electrodes has shown promise in diversifying the responses that can be elicited by retinal prostheses compared to interleaved single electrode stimulation. However, the effects of interactions between electrodes are not well understood and clinical trials with simultaneous stimulation have produced inconsistent results. We investigated the effects of multiple electrode stimulation of the retina by developing a model of cortical responses to retinal stimulation. Approach Electrical stimuli consisting of temporally sparse, biphasic current pulses, with amplitudes sampled from a bi-dimensional Gaussian distribution, were simultaneously delivered to the retina across a 42-channel electrode array implanted in the suprachoroidal space of anesthetized cats. Visual cortex activity was recorded using penetrating microelectrode arrays. These data were used to identify a linear-nonlinear model of cortical responses to retinal stimulation. The ability of the model to generalize was tested by predicting responses to non-white patterned stimuli. Main results The model accurately predicted two cortical activity measures: multi-unit neural responses and evoked potential responses to white noise stimuli. The model also provides information about electrical receptive fields, including the relative effects of each stimulating electrode on every recording site. Significance We have demonstrated a simple model that accurately describes cortical responses to simultaneous stimulation of a suprachoroidal retinal prosthesis. Overall, our results demonstrate that cortical responses to simultaneous multi-electrode stimulation of the retina are repeatable and predictable, and that interactions between electrodes during simultaneous stimulation are predominantly linear. The model shows promise for determining optimal stimulation paradigms for exploiting interactions between electrodes to shape neural activity, thereby improving outcomes for patients with retinal prostheses.

The auditory brain stem implant (ABI) is being used clinically to restore hearing to patients unable to benefit from a cochlear implant (CI). Speech perception outcomes for ABI users are typically poor compared with most CI users. The ABI is implanted either on the surface of or penetrating through the cochlear nucleus in the auditory brain stem and uses stimulation strategies developed for auditory nerve stimulation with a CI. Although the stimulus rate may affect speech perception outcomes with current stimulation strategies, no studies have systematically investigated the effect of stimulus rate electrophysiologically or clinically. We therefore investigated rate response properties and temporal response properties of single inferior colliculus (IC) neurons from penetrating ABI stimulation using stimulus rates ranging from 100 to 1,600 pulses/s in the rat. We found that the stimulus rate affected the proportion of response types, thresholds, and dynamic ranges of IC activation. The stimulus rate was also found to affect the temporal properties of IC responses, with higher rates providing more temporally similar responses to acoustic stimulation. Suppression of neural firing and inhibition in IC neurons was also found, with response properties varying with the stimulus rate. This study demonstrated that changes in the ABI stimulus rate results in significant differences in IC neuron response properties. Due to electrophysiological differences, the stimulus rate may also change perceptual properties. We suggest that clinical evaluation of the ABI stimulus rate should be performed.

Purpose: Phosphenes are the fundamental building blocks for presenting meaningful visual information to the visually impaired using a bionic eye device. The aim of this study was to characterize the size, shape, and location of phosphenes elicited using a suprachoroidal retinal prosthesis. Methods: Three patients with profound vision loss due to retinitis pigmentosa were implanted with a suprachoroidal electrode array, which was used to deliver charge-balanced biphasic constant-current pulses at various rates, amplitudes, and durations to produce phosphenes. Tasks assessing phosphene appearance, location, overlap, and the patients' ability to recognize phosphenes were performed using a custom psychophysics setup. Results: Phosphenes were reliably elicited in all three patients, with marked differences in the reported appearances between patients and between electrodes. Phosphene shapes ranged from simple blobs to complex forms with multiple components in both space and time. Phosphene locations within the visual field generally corresponded to the retinotopic position of the stimulating electrodes. Overlap between phosphenes elicited from adjacent electrodes was observed with one patient, which reduced with increasing electrode separation. In a randomized recognition task, two patients correctly identified the electrode being stimulated for 57.2% and 23% of trials, respectively. Conclusions: Phosphenes of varying complexity were successfully elicited in all three patients, indicating that the suprachoroidal space is an efficacious site for electrically stimulating the retina. The recognition scores obtained with two patients suggest that a suprachoroidal implant can elicit phosphenes containing unique information. This information may be useful when combining phosphenes into more complex and meaningful images that provide functional vision.

The aim of this study was to investigate the development of multisensory facilitation in primary school-age children under conditions of auditory noise. Motor reaction times and accuracy were recorded from 8-year-olds, 10-year-olds, and adults during auditory, visual, and audiovisual detection tasks. Auditory signal-to-noise ratios (SNRs) of 30-, 22-, 12-, and 9-dB across the different age groups were compared. Multisensory facilitation was greater in adults than in children, although performance for all age groups was affected by the presence of background noise. It is posited that changes in multisensory facilitation with increased auditory noise may be due to changes in attention bias.