Home Search Collections Journals About Contact us My IOPscience Electronic approaches to restoration of sight This content has been downloaded from IOPscience. Please scroll down to see the full text. 2016 Rep. Prog. Phys. 79 096701 (http://iopscience.iop.org/0034-4885/79/9/096701) View the table of contents for this issue, or go to the journal homepage for more Download details: IP Address: 171.64.108.170 This content was downloaded on 09/08/2016 at 17:30 Please note that terms and conditions apply. IOP Reports on Progress in Physics Reports on Progress in Physics Rep. Prog. Phys. Rep. Prog. Phys. 79 (2016) 096701 (29pp) doi:10.1088/0034-4885/79/9/096701 79 Review 2016 Electronic approaches to restoration of sight © 2016 IOP Publishing Ltd G A Goetz1,2 and D V Palanker1,3 RPPHAG 1 Hansen Experimental Physics Laboratory, Stanford University, Stanford, CA 94305, USA 2 Neurosurgery, Stanford University, Stanford, CA 94305, USA 096701 3 Ophthalmology, Stanford University, Stanford, CA 94305, USA E-mail: [email protected] and [email protected] G A Goetz and D V Palanker Received 11 November 2014, revised 11 April 2016 Accepted for publication 23 May 2016 Electronic approaches to restoration of sight Published 9 August 2016 Abstract Printed in the UK Retinal prostheses are a promising means for restoring sight to patients blinded by the gradual atrophy of photoreceptors due to retinal degeneration. They are designed to reintroduce ROP information into the visual system by electrically stimulating surviving neurons in the retina. This review outlines the concepts and technologies behind two major approaches to retinal prosthetics: epiretinal and subretinal. We describe how the visual system responds to electrical 10.1088/0034-4885/79/9/096701 stimulation. We highlight major differences between direct encoding of the retinal output with epiretinal stimulation, and network-mediated response with subretinal stimulation. We 0034-4885 summarize results of pre-clinical evaluation of prosthetic visual functions in- and ex vivo, as well as the outcomes of current clinical trials of various retinal implants. We also briefly review alternative, non-electronic, approaches to restoration of sight to the blind, and conclude 9 by suggesting some perspectives for future advancement in the field. Keywords: brain-machine interface, retinal prosthesis, neural prosthesis, electrical stimulation, neural stimulation, retina, phosphene (Some figures may appear in colour only in the online journal) 1. Introduction Intra-cellular electrical stimulation is relatively well under- stood and widely used in laboratory settings for characterizing Retinal degenerative diseases resulting in the progressive loss the electrical properties of cells. The two classical models for of photoreceptors are among the leading causes of incurable intracellular stimulation, described by the Weiss and Lapicque blindness today [1]. Retinal prostheses are designed to rein- equations, are computationally simple and supported by a troduce visual information into the neural system by stimu- wealth of experimental measurements [2, 3] (see section 3.2). lating the surviving retinal neurons electrically. Several such However, direct access to the cell cytoplasm is difficult and systems are already in clinical trials, and more advanced tech- very invasive, which makes it impractical for chronic use. nologies are being developed. This review summarizes various Developing approaches for less invasive integration of nano- approaches to retinal implants, and discusses the challenges and electrodes with cells remains an active topic of research [4]. perspectives associated with electronic restoration of sight. So far, all electro-neural interfaces used for therapeutic and diagnostic applications have relied on extracellular access to the cells for both stimulation and recording. Although theor- 1.1. Extracellular electrical stimulation as an input into the nervous system etical models for extracellular stimulation are much more complex than those for intracellular stimulation, and mech- Neural activity can be affected by modulating the membrane anisms of neural network activation less understood, there potential of neurons using electric currents, which can be is ample experimental evidence for efficacy of extracellular delivered intra- or extra-cellularly. electrical stimulation. In the central nervous system, devices 0034-4885/16/096701+29$33.00 1 © 2016 IOP Publishing Ltd Printed in the UK Rep. Prog. Phys. 79 (2016) 096701 Review that make use of it range from deep-brain stimulators for alle- filters out other components. The speech processor then passes viating symptoms associated with Parkinson’s disease, dysto- on the signals by electromagnetic induction to an implanted nia and others [5] to sensory prostheses such as cochlear [6] or receiver and stimulator, which drives electrical impulses in an retinal implants [7]. There are also multiple interfaces for the array of electrodes. The intra-cochlear array consists of 12–20 peripheral nervous system, including sacral nerve stimulation electrodes distributed along a thin cable that follows the shape for bladder control [8], lacrimal gland stimulation for secre- of the patient’s cochlea. tion of tears in dry eye disease [9], and many others. Despite a massive reduction in the number of channels Extracellular stimulation works by polarizing cells in a transmitting auditory information: no more than 20 electrodes gradient of potential created by electric currents in the extra- for 30,000 axons in the auditory nerve, the success of cochlear cellular medium. The highly conductive cell cytoplasm, sur- implants has been astounding, and it can be linked to two key rounded by a poorly conducting membrane, rapidly becomes elements. First, the electrode arrays deliver stimuli matched equipotential. This results in a decrease in trans-membrane to the natural encoding scheme of the auditory system, as they potential (also called a depolarization) in some regions, while are designed to independently stimulate different areas of other regions are concurrently hyperpolarized. Spatial dis- the cochlea that encode different spectral components of the tribution of the hyperpolarized or depolarized areas depends sound waves. Second, pre-processing modules simplify the strongly on location and orientation of the cell relative to the incoming auditory signals, which can thus be better encoded stimulating electrodes and their geometry [10, 11]. The effect with just a few electrodes in a diseased cochlea. For example, of such changes in trans-membrane potential on neural activ- pre-processing has enabled patients to recognize speech. We ity further depends on the distribution of the voltage-sensitive expect that such design decisions will be even more important ion channels over the cell membrane and on their kinetics with retinal prostheses, since the interface is two dimensional [12]. Therefore, pulse polarity, amplitude and duration need and intra-retinal signal processing is more complex. to be chosen with care to achieve the desired effects, as well as the placement, size and shape of the stimulating electrodes. 1.3. Visual processing in the retina These considerations are discussed in section 3.2. The success of cochlear implants has inspired scientists and clinicians to try restoring vision in blind patients by electrical 1.2. Cochlear implants: an exemplary success of neuroprosthetic sensory restoration stimulation of the neurons that relay visual signals to the brain. Vision begins with the projection of spatio-temporal patterns Successful restoration of hearing to the deaf with cochlear of incident light by the cornea and lens onto a thin layer of implants is the most striking example of the potential of tissue lining the back of the eye, called the retina (figures 1(a) prosthetic sensory rehabilitation. The rigorous, principled and (b)). This light-sensitive extension of the central nervous and well-developed approach to sensory restoration under- system consists of three neural layers: the photoreceptor layer, gone by cochlear implants can serve as an example for retinal the inner nuclear layer and the ganglion cell layer. prostheses. Photoreceptors are graded-response neurons (i.e. they do The structure of the inner ear is such that different frequen- not generate action potentials) that transduce photons into cies of sound waves cause sensory neurons, known as hair changes in their membrane potential by means of light-sen- cells, to vibrate in different regions of the cochlea. While sitive proteins called opsins. The vertebrate retina is inverted, high frequencies are detected at the base of the cochlea, lower so that photoreceptors are located at the back of the eye in frequencies elicit responses deeper in the cochlea. Hair cells contact with the retinal pigment epithelium (RPE), which is then transmit information about the spectral composition of essential to the health and function of the photoreceptors. RPE the sound waves via the spiral ganglion cells and the auditory cells regenerate photopigments and digest outer segments nerve to the auditory cortex. shed by the photoreceptors. Without support from the RPE, Patients with severe damage to their hair cells are pro- photoreceptor cells progressively atrophy and die. foundly deaf, but the next layer of neurons in their auditory The human retina contains about 120 million photorecep- system—the spiral ganglion cells making up the auditory tors. Cones dominate the central regions