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Recent advancements in clinical research have identified the need to combine pupillometry with a selective stimulation of the eye's photoreceptor cell types to broaden retinal and neuroretinal health assessment opportunities. Our thorough analysis of the literature revealed the technological gaps that currently restrict and hinder the effective utilization of a method acknowledged to hold great potential. The available devices do not adequately stimulate the photoreceptor types with enough contrast and do not guarantee seamless device function integration, which would enable advanced data analysis. RetinaWISE is an advanced silencing pupillometry device that addresses these deficiencies. It combines a Maxwellian optical arrangement with advanced retinal stimulation, allowing for calibrated standard measurements to generate advanced and consistent results across multiple sites. The device holds a Class 1 CE marking under EU regulation 2017/745, thus facilitating clinical research progress. [ABSTRACT FROM AUTHOR]

Functional ultrasound (fUS) flow imaging provides a non-invasive method for the in vivo study of cerebral blood flow and neural activity. This study used functional flow imaging to investigate rat brain's response to ultrasound and colored-light stimuli. Male Long-Evan rats were exposed to direct full-field strobe flashes light and ultrasound stimulation to their retinas, while brain activity was measured using high-frequency ultrasound imaging. Our study found that light stimuli, particularly blue light, elicited strong responses in the visual cortex and lateral geniculate nucleus (LGN), as evidenced by changes in cerebral blood volume (CBV). In contrast, ultrasound stimulation elicited responses undetectable with fUS flow imaging, although these were observable when directly measuring the brain's electrical signals. These findings suggest that fUS flow imaging can effectively differentiate neural responses to visual stimuli, with potential applications in understanding visual processing and developing new diagnostic tools. [ABSTRACT FROM AUTHOR]

Abstract Background Retinal degenerative diseases, e.g., retinitis pigmentosa, cause a severe decline of the visual function up to blindness. Treatment still remains difficult; however, implantation of retinal prostheses can help restoring vision. In this study, the biocompatibility and surgical feasibility of a newly developed epiretinal stimulator (OPTO-EPIRET) was investigated. The previously developed implant was extended by an integrated circuit-based optical capturing, which will enable the immediate conversion of the visual field into stimulation patterns to stimulate retinal ganglion cells. Results The biocompatibility of the OPTO-EPIRET was investigated in vitro using the two different cell lines L-929 and R28. Direct and indirect contact were analyzed in terms of cell proliferation, cell viability, and gene expression. The surgical feasibility was initially tested by implanting the OPTO-EPIRET in cadaveric rabbit eyes. Afterwards, inactive devices were implanted in six rabbits for feasibility and biocompatibility testings in vivo. In follow-up controls (1–12 weeks post-surgery), the eyes were examined using fundoscopy and optical coherence tomography. After finalization, histological examination was performed to analyze the retinal structure. Regarding the in vitro biocompatibility, no significant influence on cell viability was detected (L929:

This article presents a new design of a distributed-parameter control system for human–machine perception interface, which is capable of precisely stimulating the neural systems with electromagnetic fields. By discretising the neural systems, a state-space representation of the electromagnetic stimulation is developed to facilitate the following design and analysis. A forward controller with multiple inputs and multiple outputs is consequently designed to estimate the excitation current. This novel approach enables the applications of the well-established control theory to analyse the system. The feasibility and accuracy of the control system are numerically illustrated and validated with the applications of Transcranial Magnetic Stimulation (TMS) and retinal stimulation. The results indicate that the newly designed control system can not only generate electromagnetic stimulation with better attenuation and focality than the most widely used Figure-8 coil, but also transmit the patterns extracted from images with electromagnetic stimulations to human retinas. [ABSTRACT FROM AUTHOR]

Background: Retinal degenerative diseases, e.g., retinitis pigmentosa, cause a severe decline of the visual function up to blindness. Treatment still remains difficult; however, implantation of retinal prostheses can help restoring vision. In this study, the biocompatibility and surgical feasibility of a newly developed epiretinal stimulator (OPTO-EPIRET) was investigated. The previously developed implant was extended by an integrated circuit-based optical capturing, which will enable the immediate conversion of the visual field into stimulation patterns to stimulate retinal ganglion cells.Results: The biocompatibility of the OPTO-EPIRET was investigated in vitro using the two different cell lines L-929 and R28. Direct and indirect contact were analyzed in terms of cell proliferation, cell viability, and gene expression. The surgical feasibility was initially tested by implanting the OPTO-EPIRET in cadaveric rabbit eyes. Afterwards, inactive devices were implanted in six rabbits for feasibility and biocompatibility testings in vivo. In follow-up controls (1-12 weeks post-surgery), the eyes were examined using fundoscopy and optical coherence tomography. After finalization, histological examination was performed to analyze the retinal structure. Regarding the in vitro biocompatibility, no significant influence on cell viability was detected (L929: < 1.3% dead cells; R-28: < 0.8% dead cells). The surgery, which comprised phacoemulsification, vitrectomy, and implantation of the OPTO-EPIRET through a 9-10 mm corneal incision, was successfully established. The implant was fixated with a retinal tack. Vitreal hemorrhage or retinal tearing occurred as main adverse effects. Transitional corneal edema caused difficulties in post-surgical imaging.Conclusions: The OPTO-EPIRET stimulator showed a good biocompatibility profile in vitro. Furthermore, the implantation surgery was shown to be feasible. However, further design optimization steps are necessary to avoid intra- and postoperative complications. Overall, the OPTO-EPIRET will allow for a wide visual field and good visual acuity due to a high density of electrodes in the central retina. [ABSTRACT FROM AUTHOR]

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

Bioelectronic retinal prostheses that stimulate the remaining inner retinal neurons, bypassing degenerated photoreceptors, have been demonstrated to restore some vision in patients blinded by retinitis pigmentosa (RP). These implants encode luminance of the visual scene into electrical stimulation, however, leaving out chromatic information. Yet color plays an important role in visual processing when it comes to recognizing objects and orienting to the environment, especially at low spatial resolution as generated by current retinal prostheses. In this study, we tested the feasibility of partially restoring color perception in blind RP patients, with the aim to provide chromatic information as an extra visual cue. Case series. Seven subjects blinded by advanced RP and monocularly fitted with an epiretinal prosthesis. Frequency-modulated electrical stimulation of retina was tested. Phosphene brightness was controlled by amplitude tuning, and color perception was acquired using the Red, Yellow, Green, and Blue (RYGB) hue and saturation scaling model. Brightness and color of the electrically elicited visual perception reported by the subjects. Within the tested parameter space, 5 of 7 subjects perceived chromatic colors along or nearby the blue-yellow axis in color space. Aggregate data obtained from 20 electrodes of the 5 subjects show that an increase of the stimulation frequency from 6 to 120 Hz shifted color perception toward blue/purple despite a significant inter-subject variation in the transition frequency. The correlation between frequency and blue-yellow perception exhibited a good level of consistency over time and spatially matched multi-color perception was possible with simultaneous stimulation of paired electrodes. No obvious correlation was found between blue sensations and array placement or status of visual impairment. These findings present a strategy for the generation and control of color perception along the blue-yellow axis in blind patients with RP by electrically stimulating the retina. It could transform the current prosthetic vision landscape by leading in a new direction beyond the efforts to improve the visual acuity. This study also offers new insights into the response of our visual system to electrical stimuli in the photoreceptor-less retina that warrant further mechanistic investigation. [ABSTRACT FROM AUTHOR]

Background: Significant progress toward the recovery of useful vision in blind patients with severe degenerative retinal diseases caused by photoreceptor death has been achieved with the development of visual prostheses that stimulate the retina electrically. However, currently used prostheses do not provide feedback about the retinal activity before and upon stimulation and do not adjust to changes during the remodeling processes in the retina. Both features are desirable to improve the efficiency of the electrical stimulation (ES) therapy offered by these devices. Accordingly, devices that not only enable ES but at the same time provide information about the retinal activity are beneficial. Given the above, a bidirectional communication strategy, in which inner retinal cells are stimulated and the output neurons of the retina, the ganglion cells, are recorded using penetrating microelectrode arrays (MEAs) is proposed.Methods: Custom-made penetrating MEAs with four silicon-based shanks, each one with three or four iridium oxide electrodes specifically designed to match retinal dimensions were used to record the activity of light-adapted wildtype mice retinas and degenerated retinas from rd10 mice in vitro. In addition, responses to high potassium concentration and to light stimulation in wildtype retinas were examined. Furthermore, voltage-controlled ES was performed.Results: The spiking activity of retinal ganglion cells (RGCs) was recorded at different depths of penetration inside the retina. Physiological responses during an increase of the extracellular potassium concentration and phasic and tonic responses during light stimulation were captured. Moreover, pathologic rhythmic activity was recorded from degenerated retinas. Finally, ES of the inner retina and simultaneous recording of the activity of RGCs was accomplished.Conclusion: The access to different layers of the retina with penetrating electrodes while recording at the same time the spiking activity of RGCs broadens the use and the field of action of multi-shank and multi-site penetrating MEAs for retinal applications. It enables a bidirectional strategy to stimulate inner retinal cells electrically and to record from the spiking RGCs simultaneously (BiMEA). This opens the possibility of a feedback loop system to acknowledge the success of ES carried out by retinal prostheses.

Retinal prostheses are implantable devices that aim to restore the vision of blind patients suffering from retinal degeneration, mainly by artificially stimulating the remaining retinal neurons. Some retinal prostheses have successfully reached the stage of clinical trials; however, these devices can only restore vision partially and remain insufficient to enable patients to conduct everyday life independently. The visual acuity of the artificial vision is limited by various factors from both engineering and physiological perspectives. To overcome those issues and further enhance the visual resolution of retinal prostheses, a variety of retinal prosthetic approaches have been proposed, based on optimization of the geometries of electrode arrays and stimulation pulse parameters. Other retinal stimulation modalities such as optics, ultrasound, and magnetics have also been utilized to address the limitations in conventional electrical stimulation. Although none of these approaches have been clinically proven to fully restore the function of a degenerated retina, the extensive efforts made in this field have demonstrated a series of encouraging findings for the next generation of retinal prostheses, and these could potentially enhance the visual acuity of retinal prostheses. In this article, a comprehensive and up-to-date overview of retinal prosthetic strategies is provided, with a specific focus on a quantitative assessment of visual acuity results from various retinal stimulation technologies. The aim is to highlight future directions toward high-resolution retinal prostheses.

Understanding of the neural response to electrical stimulation requires simultaneous recording from the various neurons of retina. Electrodes form the physical interface with the neural or retinal tissue. Successful retinal stimulation and recording demands conformal integration of these electrodes with the soft tissue to ensure establishment of proper electrical connection with the excitable tissue. Mechanical impedance of polydimethylsiloxane (PDMS) being compliant with that of retinal tissue, offers excellent potential as a substrate for metal electrodes. In this paper, Cr/Au micro electrodes with 200 μm diameter were fabricated on rigid and flexible PDMS substrates under crack free condition. Spontaneous buckling of thin films over PDMS substrates improved electrode performance circumventing the fabrication issues faced over a buckled surface. Individual electrodes from the multielectrode arrays (MEAs) were examined with electrochemical impedance spectroscopy and cyclic voltammetry. Controlled fabrication process as described here generates buckles in the metal films leading to increased electrode surface area that increases the charge storage capacity and decreases the interface impedance of the metal electrodes. At 1 kHz, impedance was reduced from 490 ± 27 kΩ to 246 ± 19 kΩ and charge storage capacity was increased from 0.40 ± 0.87 mC/cm to 2.1 ± 0.87 mC/cm. Neural spikes recorded with PDMS based electrodes from isolated retina also contained less noise as indicated by signal to noise ratio analysis. The present study established that the use of PDMS as a substrate for MEAs can enhance the performance of any thin film metal electrodes without incorporation of any coating layers or nanomaterials. [ABSTRACT FROM AUTHOR]

Retinal degeneration, a leading cause of blindness worldwide, is primarily characterized by the dysfunctional/degenerated photoreceptors that impair the ability of the retina to detect light. Our group and others have shown that bioelectronic retinal implants restore useful visual input to those who have been blind for decades. This unprecedented approach of restoring sight demonstrates that patients can adapt to new visual input, and thereby opens up opportunities to not only improve this technology but also develop alternative retinal stimulation approaches. These future improvements or new technologies could have the potential of selectively stimulating specific cell classes in the inner retina, leading to improved visual resolution and color vision. In this review we will detail the progress of bioelectronic retinal implants and future devices in this genre as well as discuss other technologies such as optogenetics, chemical photoswitches, and ultrasound stimulation. We will discuss the principles, biological aspects, technology development, current status, clinical outcomes/prospects, and challenges for each approach. The review will cover functional imaging documented cortical responses to retinal stimulation in blind patients. [ABSTRACT FROM AUTHOR]

Focal stimulation of neural tissue is a challenge in retinal prosthetic devices in which the aim is to improve the spatial resolution of the stimulation and therefore increase the electrode density of the prosthetic devices. Our work intends to create a new implant able to enhance the focalisation of the stimulation signal through protuberant electrodes. These electrodes are micro fabricated on a soft polyimide substrate using classical metal electrodeposition techniques. Before proceeding with fabrication a FEM model of the electrode’s current density was done to select the best-performing structures and geometries in terms of local stimulation. Based on these models, several prototypes were fabricated and implanted in vivo into a rat’s eye to verify the adaptation to the retina tissue.

Objective. Retinal prostheses use electric current to activate inner retinal neurons, providing artificial vision for blind people. Epiretinal stimulation primarily targets retinal ganglion cells (RGCs), which can be modeled with cable equations. Computational models provide a tool to investigate the mechanisms of retinal activation, and improve stimulation paradigms. However, documentation of RGC model structure and parameters is limited, and model implementation can influence model predictions. Approach. We created a functional guide for building a mammalian RGC multi-compartment cable model and applying extracellular stimuli. Next, we investigated how the neuron's three-dimensional shape will influence model predictions. Finally, we tested several strategies to maximize computational efficiency. Main results. We conducted sensitivity analyses to examine how dendrite representation, axon trajectory, and axon diameter influence membrane dynamics and corresponding activation thresholds. We optimized the spatial and temporal discretization of our multi-compartment cable model. We also implemented several simplified threshold prediction theories based on activating function, but these did not match the prediction accuracy achieved by the cable equations. Significance. Through this work, we provide practical guidance for modeling the extracellular stimulation of RGCs to produce reliable and meaningful predictions. Robust computational models lay the groundwork for improving the performance of retinal prostheses., (Creative Commons Attribution license.)

• It is the first time to investigate the responses arising in visual cortex to sinusoidal retinal electrostimulation, and to compare the different cortical responses elicited by sinusoidal and rectangular waveforms in vivo. • The optimal stimulation frequency for sinusoidal retinal electrostimulation was approximately 20 Hz. • Sinusoidal retinal electrostimulation is a more efficient strategy than rectangular stimulation in regard to cortical response, especially at low frequency. Retinal stimulation has become a widely utilized approach to restore visual function for individuals with retinal degenerative diseases. Although the rectangular electrical pulse is the primary stimulus waveform used in retinal neuromodulation, it remains unclear whether alternate waveforms may be more effective. Here, we used the optical intrinsic signal imaging system to assess the responses of cats' visual cortex to sinusoidal electrical stimulation through contact lens electrode, analyzing the response to various stimulus parameters (frequency, intensity, pulse width). A comparison between sinusoidal and rectangular stimulus waveform was also investigated. The results indicated that the optimal stimulation frequency for sinusoidal electrical stimulation was approximately 20 Hz, supporting the hypothesis that low-frequency electrostimulation induces more responsiveness in retinal neurons than high-frequency electrostimulation in case of sinusoidal stimulation. We also demonstrated that for low-frequency retinal neuromodulation, sinusoidal pulses are more effective than rectangular ones. In addition, we found that compared to current intensity, the effect of the sinusoidal pulse width on cortical responses was more prominent. These results suggested that sinusoidal electrical stimulation may provide a promising strategy for improved retinal neuromodulation in clinical settings. [ABSTRACT FROM AUTHOR]

Retinal prostheses are implantable devices that aim to restore the vision of blind patients suffering from retinal degeneration, mainly by artificially stimulating the remaining retinal neurons. Some retinal prostheses have successfully reached the stage of clinical trials; however, these devices can only restore vision partially and remain insufficient to enable patients to conduct everyday life independently. The visual acuity of the artificial vision is limited by various factors from both engineering and physiological perspectives. To overcome those issues and further enhance the visual resolution of retinal prostheses, a variety of retinal prosthetic approaches have been proposed, based on optimization of the geometries of electrode arrays and stimulation pulse parameters. Other retinal stimulation modalities such as optics, ultrasound, and magnetics have also been utilized to address the limitations in conventional electrical stimulation. Although none of these approaches have been clinically proven to fully restore the function of a degenerated retina, the extensive efforts made in this field have demonstrated a series of encouraging findings for the next generation of retinal prostheses, and these could potentially enhance the visual acuity of retinal prostheses. In this article, a comprehensive and up-to-date overview of retinal prosthetic strategies is provided, with a specific focus on a quantitative assessment of visual acuity results from various retinal stimulation technologies. The aim is to highlight future directions toward high-resolution retinal prostheses. [ABSTRACT FROM AUTHOR]

Highlights from the article: Biomedical Applications: Ultrasound-Induced Wireless Energy Harvesting for Potential Retinal Electrical Stimulation Application (Adv. Funct. In article number 1902522, Yang Yang, Jianguo Zhu, Yong Chen, Qifa Zhou, and co-workers demonstrate a potential retinal electrical stimulation strategy using ultrasound-driven wireless energy harvesting technology through a millmeter-scale lead-free ultrasonic energy harvesting device. The as-developed device is flexible and can be attached on a complex surface and be driven by ultrasound to produce adjustable electrical outputs.

Retinal electrical stimulation for people with neurodegenerative diseases has shown to be feasible for direct excitation of neurons as a means of restoring vision. In this work, a new electrical stimulation strategy is proposed using ultrasound‐driven wireless energy harvesting technology to convert acoustic energy to electricity through the piezoelectric effect. The design, fabrication, and performance of a millimeter‐scale flexible ultrasound patch that utilizes an environment‐friendly lead‐free piezocomposite are described. A modified dice‐and‐fill technique is used to manufacture the microstructure of the piezocomposite and to generate improved electrical and acoustic properties. The as‐developed device can be attached on a complex surface and be driven by ultrasound to produce adjustable electrical outputs, reaching a maximum output power of 45 mW cm−2. Potential applications for charging energy storage devices and powering commercial electronics using the device are demonstrated. The considerable current signals (e.g., current >72 µA and current density >9.2 nA µm−2) that are higher than the average thresholds of retinal stimulation are also obtained in the ex vivo experiment of an implanted environment, showing great potential to be integrated on implanted biomedical devices for electrical stimulation application. [ABSTRACT FROM AUTHOR]