Akos Kusnyerik

Subretinal electronic chips allow blind patients to read letters and combine them to words

A light-sensitive, externally powered microchip was surgically implanted subretinally near the macular region of volunteers blind from hereditary retinal dystrophy. The implant contains an array of 1500 active microphotodiodes (‘chip’), each with its own amplifier and local stimulation electrode. At the implants tip, another array of 16 wire-connected electrodes allows light-independent direct stimulation and testing of the neuron–electrode interface. Visual scenes are projected naturally through the eyes lens onto the chip under the transparent retina. The chip generates a corresponding pattern of 38 × 40 pixels, each releasing light-intensity-dependent electric stimulation pulses. Subsequently, three previously blind persons could locate bright objects on a dark table, two of whom could discern grating patterns. One of these patients was able to correctly describe and name objects like a fork or knife on a table, geometric patterns, different kinds of fruit and discern shades of grey with only 15 per cent contrast. Without a training period, the regained visual functions enabled him to localize and approach persons in a room freely and to read large letters as complete words after several years of blindness. These results demonstrate for the first time that subretinal micro-electrode arrays with 1500 photodiodes can create detailed meaningful visual perception in previously blind individuals.

Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS

This study aims at substituting the essential functions of photoreceptors in patients who are blind owing to untreatable forms of hereditary retinal degenerations. A microelectronic neuroprosthetic device, powered via transdermal inductive transmission, carrying 1500 independent microphotodiode-amplifier-electrode elements on a 9 mm2 chip, was subretinally implanted in nine blind patients. Light perception (8/9), light localization (7/9), motion detection (5/9, angular speed up to 35 deg s−1), grating acuity measurement (6/9, up to 3.3 cycles per degree) and visual acuity measurement with Landolt C-rings (2/9) up to Snellen visual acuity of 20/546 (corresponding to decimal 0.037 or corresponding to 1.43 logMAR (minimum angle of resolution)) were restored via the subretinal implant. Additionally, the identification, localization and discrimination of objects improved significantly (n = 8; p < 0.05 for each subtest) in repeated tests over a nine-month period. Three subjects were able to read letters spontaneously and one subject was able to read letters after training in an alternative-force choice test. Five subjects reported implant-mediated visual perceptions in daily life within a field of 15° of visual angle. Control tests were performed each time with the implants power source switched off. These data show that subretinal implants can restore visual functions that are useful for daily life.

Spatial Resolution and Perception of Patterns Mediated by a Subretinal 16-Electrode Array in Patients Blinded by Hereditary Retinal Dystrophies

PURPOSEnThe perception of 11 persons blinded by hereditary retinal degeneration elicited by a subretinally implanted 16-electrode array used for light-independent direct stimulation of the retina is described. This device is part of the Tübingen retina implant, which also employs a light-sensitive, multiphotodiode array (MPDA). The ability to reliably recognize complex spatial percepts was investigated.nnnMETHODSnEleven blind volunteers received implants and participated in standardized psychophysical tests investigating the size and shape of perceptions elicited by single-electrode activation, multiple-electrode activation, and activation of compound patterns such as simplified letters.nnnRESULTSnVisual percepts were elicited reliably in 8 of 11 patients. On single-electrode activation, percepts were generally described as round spots of light of distinguishable localization in the visual field. On activation of a pattern of electrodes, percepts matched that pattern when electrodes were activated sequentially. Patterns such as horizontal or vertical bars were identified reliably; the most recent participant was able to recognize simplified letters presented on the 16-electrode array. The smallest distance between sites of concurrent retinal stimulation still yielding discernible spots of light was assessed to be 280 μm, corresponding to a logMAR of 1.78.nnnCONCLUSIONSnSubretinal electric stimulation can yield reliable, predictable percepts. Patterned perception is feasible, enabling blind persons to recognize shapes and discriminate different letters. Stimulation paradigms must be optimized, to further increase spatial resolution, demanding a better understanding of physical and biological effects of single versus repetitive stimulation (ClinicalTrials.gov number, NCT00515814).

Functional Outcome in Subretinal Electronic Implants Depends on Foveal Eccentricity

PURPOSEnAn active microelectronic subretinal implant, developed to replace the photoreceptive function in hereditary degenerations of the outer retina, has been applied in a pilot and clinical study in patients with end-stage retinal degeneration.nnnMETHODSnThe study population comprised 20 blind patients, all of whom lost vision as result of a hereditary retinal disease. An active visual implant was placed surgically within the subretinal space of each patient: subfoveal placement in eight patients (group 1) and parafoveal placement in 12 (group 2). Standardized low-vision tests, including light perception, light localization, movement detection, grating acuity, and visual acuity by Landolt C-rings, were used under masked, randomized implant-OFF and implant-ON conditions. For the chip-mediated vision functional results of both subject groups were compared.nnnRESULTSnThree of 20 patients were excluded from analysis because of surgical or technical implant issues. Among patients with nonfoveal placement of the implant, 80% could perceive light, 10% recognized location, and 10% correctly distinguished stripe patterns up to a resolution of 0.33 cycles/degree. No nonfoveal placement patient passed the motion or Landolt C-ring tests. When the implant was placed subfoveally, 100% of patients could perceive light and determine light localization, 75% could resolve motion up to 35°/s, 88% correctly distinguished stripe patterns up to a resolution of 3.3 cycles/degree, and 38% passed a Landolt C-ring test with a decimal visual acuity of up to 20/546 (logMAR 1.43).nnnCONCLUSIONSnSubfoveal placement of active subretinal visual implants allows superior measurable outcomes compared to para- or nonfoveal placement locations. (ClinicalTrials.gov numbers, NCT01024803, NCT00515814.).

Safety and efficacy of subretinal visual implants in humans: methodological aspects

Replacing the function of visual pathway neurons by electronic implants is a novel approach presently explored by various groups in basic research and clinical trials. The novelty raises unexplored methodological aspects of clinical trial design that may require adaptation and validation.

Positioning of electronic subretinal implants in blind retinitis pigmentosa patients through multimodal assessment of retinal structures

PURPOSEnTo optimize methods for positioning subretinal visual implants, customizing their cable length, guiding them to the predetermined retinal position, and evaluating their performance.nnnMETHODSnTen eyes of 10 patients (6 male, 4 female, mean age 46.4 years) were investigated before implantation of a subretinal visual implant. The structural characteristics of the retina as well as the ocular dimensions were determined. Topographic images of the prospective implantation site were subdivided into grids of squares. Each square received a weighted score for suitability. The sum of the scores was calculated, and the region with the highest score was chosen for the implant. In each case, the implants power supply cable length was calculated by means of magnetic resonance imaging. The planned and achieved positions before and after implantation were compared.nnnRESULTSnThe mean light sensitivity ratio between the area actually covered by the chip and that of the planned position was 90.8% with an SD of 11.4%. In two cases with almost perfect positioning, the computed ratio was 100%. Measurements showed that to achieve a 95% sensitivity rate the difference between the planned and achieved chip position must be less than 1.7 mm. Preoperative calculations of the intraocular cable length proved accurate in all cases.nnnCONCLUSIONSnPreoperative evaluation of retinal structures and eye morphology is useful for guiding a retinal implant to the designated area. It is a meaningful tool for planning and performing retinal chip implantation, and it optimizes personalized implantation. (ClinicalTrials.gov numbers, NCT00515814, NCT01024803.).

Vision restoration with implants in retinal degenerations

Up until now there has been no available treatment for diseases causing the permanent impairment of retinal photoreceptors. Currently the development of the retinal prostheses is the earliest to promise a result that can be implemented in the clinical treatment of these patients. Implants with different operating principles and in various stages of progress are presented in details, highlighting the characteristics, as well as the Hungarian aspects of the development. This survey intends to provide an overview on retinal prostheses, implantable in case of degenerative diseases of the retina, by reviewing and assessing the papers published in relevant journals and based on personal experience. Developments in microelectronics in recent years made it possible and proved to be feasible to replace the degenerated elements in the retina with electrical stimulation. Multiple comparable approaches are running simultaneously. Two types of these implants are directly stimulating the remaining living cells in the retina. Hitherto the finest resolution has been achieved with the subretinal implants. Although the epiretinal implant offer lower resolution, but requires shorter surgery for implantation. Retinal implants in certain retinal diseases are proved to be capable of generating vision-like experiences. A number of types of retinal implants can be expected to appear in clinical practice a few years after the successful conclusion of clinical trials.

Targeting neuronal and glial cell types with synthetic promoter AAVs in mice, non-human primates, and humans

Targeting genes to specific neuronal or glial cell types is valuable both for understanding and for repairing brain circuits. Adeno-associated viral vectors (AAVs) are frequently used for gene delivery, but targeting expression to specific cell types is a challenge. We created a library of 230 AAVs, each with a different synthetic promoter designed using four independent strategies. We show that ~11% of these AAVs specifically target expression to neuronal and glial cell types in the mouse retina, mouse brain, non-human primate retina in vivo, and in the human retina in vitro. We demonstrate applications for recording, stimulation, and molecular characterization, as well as the intersectional and combinatorial labeling of cell types. These resources and approaches allow economic, fast, and efficient cell-type targeting in a variety of species, both for fundamental science and for gene therapy.