Artificial human vision - CiteSeerX

Review

Artificial human vision Jason Dowling

CONTENTS

Can vision be restored to the blind? As early as 1929 it was discovered that stimulating the visual cortex of an individual led to the perception of spots of light, known as phosphenes [1]. The aim of artificial human vision systems is to attempt to utilize the perception of phosphenes to provide a useful substitute for normal vision. Currently, four locations for electrical stimulation are being investigated; behind the retina (subretinal), in front of the retina (epiretinal), the optic nerve and the visual cortex (using intra- and surface electrodes). This review discusses artificial human vision technology and requirements and reviews the current development projects.

Blindness & mobility defined

Expert Rev. Med. Devices 2(1), xxx–xxx (2005)

AHV technology & requirements Cortical stimulation Retinal stimulation Optic nerve devices AHV simulation studies Expert opinion Five-year view Information resources Key issues References Affiliation

Queensland University of Technology, School of Electrical and Electronic Systems Engineering, Faculty of Built Environment and Engineering,, Brisbane, Australia Tel: +617 3864 1608 Fax: +617 3864 1516 [email protected] KEYWORDS: artificial human vision, bionic eye, blind mobility, cortical stimulation, epiretinal stimulation, subretinal stimulation, visual prosthesis

www.future-drugs.com

Blindness & mobility defined Blindness

prevented, the federal budget would save US$1 billion per year [6].

In 1997 the World Health Organization estimated that there were close to 150 million individuals with significant visual disability (or legally blind) worldwide, with 38 million of those totally blind (without light perception) [2]. In economically developed societies, the leading cause of blindness and visual disability in adults is diabetic retinopathy. The most common nonpreventable cause of blindness in the developed world is age- related macular degeneration, which occurs in 25% of individuals 80 years of age and over [3]. Retinitis pigmentosa (RP) is a condition characterized by a gradual loss of the visual field, leading to the loss of peripheral vision and eventually to blindness. Approximately 90% of blind people live in the developing world. In general, more than twothirds of today’s blindness could be prevented or treated by applying existing knowledge and technology [4]. Nearly half of all blindness is due to cataract and a quarter of the world’s blindness is due to trachoma. Other major causes of blindness are glaucoma (a group of eye diseases characterized by an increase in intraocular pressure), trachoma and onchocerciasis (both parasitic diseases) and xerophthalmia (caused by vitamin A deficiency) [5]. It has been estimated that if all avoidable blindness in the USA in individuals under the age of 20 and working-age adults were 10.1586/17434440.2.1.xxx

Blind mobility

Blind mobility is affected by physical and mental health factors, such as multiple disabilities. Age is a mobility issue as many of the blind are elderly, which can restrict their ability to use some mobility aids (such as a guide dog). Many congenitally blind children have hypotonia or abnormally low muscle tone (due to delayed sensorimotor development) which can affect mobility [7]. An additional problem, experienced by most blind patients without light perception, is falling out of phase with the 24 h day which often leads to severe sleep disorders. In 1996, The US National Research Council published the following summary of blind pedestrian needs in 1996 [8]: • Detection of obstacles in the travel path from ground level to head height for the full body width • Travel surface information • Detection of objects bordering the travel path • Distant object and cardinal direction information • Landmark location and identification information • Information enabling self-familiarization and mental mapping of an environment

© 2005 Future Drugs Ltd.

ISSN 1743-4440

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Most existing mobility aids for the blind provide information in either tactile or auditory form. The two most widely used devices are the long cane and the guide dog, however, these devices have limitations; the long cane is only effective over a short range and a guide dog requires expensive training and maintenance. A number of electronic travel aids (ETAs) have also been developed, generally using ultrasound or lasers. These devices have usually failed commercially due to their expense, lack of benefit in improved mobility and cosmetic unattractiveness [9]. The objective assessment of technical aids for the blind (e.g., using Percentage of Preferred Walking Speed [10]) could provide useful information during device development and for consumers. AHV technology & requirements

The development of an artificial human vision (AHV) system is a multidisciplinary field, involving inputs from neuroscience, engineering, computer science and ophthalmology, in addition to orientation and mobility specialists. With the exception of subretinal prostheses, most AHV systems have similar system requirements. The main components, which will need to function in real time, are: • A Camera – required to capture and digitize image information from the environment. Charged Coupled Device (CCD)-based digital cameras are inexpensive, small and can be easily interfaced to other system components. An adaptive mechanism (such as an automatic gain in current video cameras) will also be required to allow the device to function at different levels of illumination [11]. CCD camera sensors have a linear response to light intensity. A logarithmic camera has a similar response to the human visual system and can reduce saturation in high contrast visual scenes. The use of a logarithmic camera in an AHV is being investigated in at least one current research project [12]. • Image processing – there will be more data retrieved from the camera than can be used in an AHV device. The image data will usually be preprocessed to reduce noise. After this, an information reduction (such as edge detection or segmentation) or a scene understanding approach, attempting to extract information, can be used. Cortical prosthesis research by the Dobelle Institute (Portugal) has found that edge detection and image reversal enhance the ability of subjects to recognize important scene components (such as doorways) [13]. An alternate, and alternative, approach to traditional image processing is the use of neuromorphic vision systems, designed to mimic the design of the human visual system [14]. • Transmitter/receiver – a link is required from the camera/image processing components to the stimulator and electrode array, which are usually located inside the body. Percutaneous connections have been used for most research due to their simplicity and reliability [15], however, the risk of chronic infection is higher with this type of connection. The Dobelle Institute system uses a percutateous connecting pedestal for connection to the image processing unit (a notebook PC). A transcutaneous connection, as used in cochlear implants, uses

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radiofrequency telemetry to send data and power to the embedded stimulator, reducing the risk of infection. Most AHV research projects plan to eventually use transcutaneous connections. Reverse telemetry can also be used to provide details of stimulation voltage waveforms, impedance measurements and reconstruction of stimulation voltage waveforms [16]. A good description of a high efficiency transcutaneous data link for implanted electronic devices is provided by Troyke and Schwan [17]. • Stimulator/electrodes – an electrode is a thin wire, which allows a small amount of precisely controlled electrical current to pass through it. Electrodes can be used for either stimulation or recording the electrical activity of the brain. The purpose of the stimulator is to send current through multiple electrodes. There are two main types of electrodes discussed in the AHV literature; surface electrodes, which lie flat against the stimulation/recording target and penetrating electrodes, which are inserted inside the stimulation/recording target. The biocompatability, long-term effectiveness and safe threshold levels for implanted electrodes need to be carefully considered. Cortical stimulation

In the functioning human vision system, two types of photoreceptors in the retina (rods and cones) are activated by light, which has been focused by the lens and cornea in the eye. Electrical signals from these photoreceptors are then processed through a layer of bipolar and ganglion cells within the retina, before passing to the optic nerve [18]. The amount of information entering the eye is reduced considerably - there are over 120 million photoreceptors and only about 1 million ganglion cells [19]. Most of the signals from the optic nerve pass through the lateral geniculate body to the visual cortex, although, approximately 20–30% of fibers connect to the superior colliculus, which appears to be responsible for eye movements [20]. Cortical-based AHV systems use either surface or intracortical stimulation, using penetrating electrodes. Cortical stimulation is the only treatment available for blindness caused by glaucoma, optic atrophy or diseases of the central visual pathways, such as brain injuries or stroke. The main negative feature of a cortical implant is the lack of preliminary processing by the brain, particularly in the retina where much of the information reduction takes place. Most research regarding AHV has focused on sending a captured image to the brain as a bitmap representation. The bitmap approach to cortical devices has been questioned [21]. Research performed by Hubel and Weisel in macaque monkeys has found that, in addition to spatial location of a stimulus in the visual field, neurons in the visual cortex are selective for spatial, temporal, chromatic and binocular cues [22]. A greater knowledge of cortical physiology may be required before a cortical prosthesis provides useful vision. Evidence has also been found to suggest that there may be specialized cortical areas for the analysis of biologically important images (such as faces) [23].

Expert Rev. Med. Devices 2(1), (2005)

Artificial human vision

Cortical surface stimulation

Bionic eye research project

The early developments in cortical prostheses involved surface electrode arrays. The first person to expose the human occipital pole to electrical stimulation was the German researcher Forester in 1929, who noticed that stimulation caused the subject to see a spot of light in a position that depended on the site of stimulation [1].

Although research in the early 1990s moved towards intracortical stimulation, a recently commenced project at the University of New South Wales ([NSW], Australia) is investigating the use of technology adapted from cochlear implants (which generally use surface electrodes). An in vivo model has been reported, in which the transcallosal evoked response to cortical stimulation on the opposite hemisphere. Future psychophysical experiments in a human subject are planned [28,29].

Brindley & Lewin

Brindley and Lewin published the results of a groundbreaking study on cortical stimulation in 1968. In their study, a 52-year-old legally blind subject was implanted with an array of 80 platinum electrodes, a design which had previously been tested in baboons. These electrodes were stimulated by pulsed radio signals from an oscillator. Stimulation of these electrodes produced discernible phosphenes [24]. Brindley and Lewin suggested that there was probably no flicker fusion frequency for this implant. They also found that phosphenes moved with eye movements and that phosphene perception usually (but not always) stopped when stimulation ceased. Stimulation of one electrode was found to produce multiple phosphenes and when multiple electrodes in close vicinity were activated, a larger, straight light phosphene was produced. Unfortunately, the monophasic stimulus pulses used long-term in these earlier studies were also likely to cause irreversible damage at the electrode-tissue interface [25]. Dobelle & Mladejovsky

Brindley and Lewin’s research inspired pioneering work involving 37 human subjects by Dobelle and Mladejovsky in 1974, where electrical stimulation was applied to patients hospitalized for cranial surgery [26]. Supporting Brindley and Lewin’s work, they found eye movements caused phosphenes to move and multiple phosphenes could be produced from a single electrode. However, Dobelle and Mladejovsky found that constant stimulation caused phosphenes to fade, suggesting that phosphenes need to be refreshed. In a later paper, it was reported that subjects were able to read electrodeinduced Braille characters more efficiently than using their tactile sense [27]. In 2000, Dobelle published a paper describing a subject who had been using a cortical visual prosthesis system for over 20 years [13]. The system used a 64-channel electrode array, which had been implanted on the mesial surface of the subject’s right occipital lobe in 1978. When stimulated, each electrode produced one to four closely spaced phosphenes. The stimulation parameters and phosphene locations had been stable for the past 20 years, however, the electrode thresholds required a 15-min recalibration every morning. This system utilized a black and white camera connected to a notebook computer. Cables from the notebook were connected to a percutaneous connecting pedestal, which interfaced to the microcontroller, stimulus generator and electrode array. Dobelle reported that frame rates of around 4 fps have been found to be optimal. The subject has a visual acuity of approximately 20/200.


Intracortical stimulation National Institute of Health

The Neuroprosthesis Program at the US National Institute of Health (NIH) was the first to publish research concerning the use of intracortical stimulation to produce phosphenes. In this study by Bak and colleagues, three normally sighted patients, undergoing occipital craniotomies for other conditions, were tested for an hour each [30]. Surface stimulation produced the same phosphenes described by Dobelle and Brindley. Following this, a dual microelectrode was inserted to level 4B in the primary visual cortex and stimulation applied. Unlike surface electrodes, the intracortical electrode phosphenes did not flicker. An important finding from this research was the discovery that intracortical stimulation required 10–100 times less electrical current to produce phosphenes than surface electrodes. In addition, intracortical electrodes located as closely as 500 µm could evoke distinct phosphenes. A more detailed experiment by the NIH team was described in 1996 by Schmidt and colleagues [31]. 38 microelectrodes were inserted into the right visual cortex of a 42-year-old woman for 4 months. The patient, who had been blind for 22 years, was consistently able to perceive phosphenes at stable positions in visual space. Phosphenes were produced with 34 of the microelectrodes, at thresholds usually at 25 µA. It was found that these phosphenes did not flicker and changing the stimulus amplitude, frequency and pulse duration could change phosphene brightness. A perception of depth from the stimulation was also reported and as the stimulation level was increased, the phosphenes generally changed color (white, yellowish and grayish). Supporting earlier research, phosphenes moved with eye movements. Schmidt and colleagues suggested that electrodes could be placed five times closer than surface stimulation. An important result of this study concerned afterdischarge; one phosphene was observed for up to 25 min after cessation of stimulation, which suggests that even small electrical currents from repeated, patterned stimulation may be epileptogenic. At least six of the electrode leads broke during the study, due to accidental movement of the patient during sleep, which limited testing on pattern recognition. The percutaneous leads and electrodes were removed after 4 months. The NIH Neuroprosthesis Program was discontinued by 2001 [32]. However, there is continuing collaboration with the intracortical visual prosthesis team at the Illinois Institute of Technology (IL, USA).

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University of Utah

The University of Utah (UT, USA) currently has an active intracortical research group led by Richard Normann. This team has focused mainly on electrode array design for stimulation and recording, behavioral experiments and psychophysical experiments. The University of Utah has developed an array of 100 penetrating cortical electrodes, each 1.5 mm in length and separated by 400 µ. This length has been selected to reach level 4Cb of the visual cortex, where neurons have the smallest and simplest receptive fields and where lower thresholds can be used for generating phosphenes [33]. Manual insertion of the array was found to cause cortical deformation, therefore, a pneumatic insertion device has also been developed and tested [34]. The biocompatibility of this array has been extensively evaluated and arrays have been inserted for up to 14 months in cats [35]. The Utah electrode array (UEA) has been investigated as a recording structure for potential brain-computer interfaces [36] and recently for investigating representations of simple visual stimuli in the cat visual cortex [37]. A modification of the UEA is available which has graded electrodes, allowing stimulation and recording to be conducted in both horizontal and vertical directions [38]. Cortical implant for the blind

The Cortical Implant for the Blind (CORTIVIS) project, commenced in 2001, is lead by Edwardo Fernandez of the University of Miguel Hernandez (Spain), and involves researchers from Spain, Germany, Austria, France and Portugal. The group has investigated the use of the UEA in animal experiments (cats, rabbits and rats) over a period of 12 h to 6 months. The electrodes were found to be well-tolerated by the cortex, despite some inflammatory responses in the vicinity of the electrode tracks [39]. In order to develop a methodology to identify feasibility of a cortical prosthesis for a patient and the preferred location for the prosthesis, Fernandez and colleagues have used transcranial magnetic stimulation (TMS) to evoke phosphenes in 13 legally blind and 19 normally sighted patients [40]. The advantage of TMS is that it is painless and noninvasive. In total, 28-positions arranged in a 2 × 2 cm grid over the occipital area were stimulated and phosphenes were perceived by 94% of the normally sighted participants. However, only 54% of the legally blind patients perceived phosphenes (even after adjusting the stimulation parameters). Evoked phosphenes were topographically organized and the mapping results could generally be reproduced between participants. The CORTIVIS project is also developing a retina-like processor, designed to simulate the functioning of the human retina to produce optimal electrode stimulation at the cortical level [41]. The output of this system is a series of spike patterns, which could be used to stimulate neurons in the visual cortex. In a study of brain plasticity by the CORTIVIS group, fMRI was used to study the differences in reading Braille in normally sighted and congenitally blind people [42]. Unlike normally

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sighted participants, activation of the occipital cortex was recorded in blind participants. The authors note that where cross modal plasticity has been activated in this way, the processing of tactile information is associated with significantly improved tactile reading skill. Intracortical visual prosthesis

The intracortical visual prosthesis (Illinois Institute of Technology) project is led by Philip R Troyk, Director of the Laboratory of Neuroprosthetic Research, and involves collaboration with other institutions and former staff from the NIH Neuroprosthesis Program. Their approach is to use small implanted arrays (consisting of eight electrodes) in groups of intracortical electrodes which tile the visual cortex. In a recent paper, Troyke and colleagues describe an interesting animal experiment, using a male macaque, designed to investigate visual prosthesis functioning with this tiled design [21]. Prior to implantation, the animal was presented with a flash of light, and then trained to continue staring at the flash location (so only the memory of the flash remains); 192 tiled electrodes were then implanted into area V1 of the animal. Only 114 electrodes were functioning post implantation. The receptive field coordinates for each implanted electrode were estimated and a phosphene was generated in that location. The macaque received a reward if its eye position moved within 2° of the known receptive field for that electrode. Retinal stimulation

The most common nonpreventable reason for blindness in the developed world is age-related macular degeneration. This condition affects the retina at the back of the eye, while leaving the remaining components of the visual system intact. Retinal prosthesis research aims to use the remaining visual pathway components to provide partial restoration of sight. An Australian researcher, in 1956, was the first to describe placing a light sensitive selenuium plate behind the retina of a blind individual and restoring some intermittent light sensation [43]. There are significant advantages to the retinal approach to AHV. Implantation of a cortical prosthesis requires intercranial neurosurgery, which may expose a patient to higher risk. At a fine scale, the mapping of a stimulus to the appropriate place on the cortex may be variable between subjects [44]. An alternate approach is to stimulate the eye rather than the brain. A retinal prosthesis could assist people who still have a functioning optic nerve. In post-mortem examinations of people without light perception, 80% of the optic nerve and approximately 30% of the ganglion cell layer was found to be functioning [45]. However, there may also be continual remodeling by the retina which could lead to spatial corruption and cryptic synapse formation after a retinal implant has been attached [46]. The two types of retinal prosthesis, discussed in the following sections, are subretinal and epiretinal. Subretinal stimulation

There are approximately 130 million receptors in the retina, which are reduced down to 1 million fibers in of the optic



nerve. This information reduction takes place in the inner nuclear layer (consisting of amacrine, bipolar and horizontal cell nuclei) of the retina. Targeting this layer, a subretinal implant is located behind the photoreceptor layer of the retina and in front of the pigmented layer called the retinal pigment epithelium. Therefore, the subretinal approach, unlike the epiretinal, may be capable of utilizing the information reduction functions in the retina, provided the electric field produced does not interfere with other retina components (such as the ganglion cell layer). Optobionics Corp.

Since the 1980s Alan and Vincent Chow have been investigating subretinal microphotodiodes for subretinal stimulation [47] and their company, Optobionics Corp. (USA), was awarded the original patent for an artificial subretinal device in 1991 [48]. In an early animal experiment, an implanted strip electrode was inserted behind the photoreceptor layer in a rabbit’s eye. The evoked electrical response of stimulation to the operated eye was compared with the normal eye by presenting a flash of light and then measuring the response from the scalp over the visual cortex. It was found that a brief electrical spike was generated during stimulation [49]. This experiment demonstrated the feasibility of converting light into electrical energy using subretinal stimulation to produce a cortical electrical evoked response [50]. A further animal experiment focused on the long-term biocompatibility of subretinal stimulation [51]. Cats were selected for this study as they have both retinal and choroidal circulation (unlike rabbits). The implants, approximately 50 µm in thickness, with a diameter of 2–2.5 mm, consisted of a doped and ion implanted silicon substrate, surrounded by a gold electrode layer. Following implantation in the cat’s right eye, the arrays were evaluated over 10 to 27 months. During this time, a gradually decreased response to light was found, due to the dissolution of the gold electrode layer. In addition, the silicon substrate blocked choroidal nourishment to the retina, which led to a degeneration of the photoreceptors, which are highly dependent on blood supply for oxygenation. The loss of photoreceptors may not be important as they may be damaged anyway. However, design work commenced on a fenestrated design in order to improve the flow of nutrients from the choroid to the retina [51]. The positive findings from this study were that the implant maintained a stable position over time and there was no rejection, inflammation or degeneration of the retina outside the location of the implant [52]. By June 2000, Optobionics received approval from the US Food and Drug Administration (FDA) to commence safety and feasibility trials in six patients [53]. The artifical silicon retina (ASR), consisting of 5000 microelectrode-tipped microphotodiodes in a 2-mm diameter device, was implanted into the right eyes of six legally blind patients with RP. During a follow-up period of 6–18 months, all ASRs were found to function electrically and there were no signs of rejection, inflammation, erosion, retinal detachment or migration of the device. During this


study it was found that all patients experienced improvements in visual function (such as improved color perception) and there were also unexpected improvements in retinal areas distant from the implant. These improvements may have been due to neurotropic effects, rather than the device and further studies are intended to explore this improvement. Additional planned research will examine the implant and age-related macular degeneration, and whether the neurotropic effect can be effective in earlier stages of RP [53]. An issue with the Optobionics research has been the lack of an experimental control (by implanting an inactive device or conducting sham surgery) to evaluate against the ASR. Pardue and colleagues have recently conducted research addressing this issue [54]. Their experiment involved 15 RCS rats, which have a genetic mutation resulting in photoreceptor degeneration over approximately 77 days. The rats received either the ASR device, an inactive device, sham surgery or no surgery. The outer retinal function was assessed with weekly electroretinogram (ERG) recordings. After 4–6 weeks there was a 30–70% higher b-wave amplitude response with the ASR compared with the inactive device, indicating that the ASR device appears to produce some temporary improvement in retinal function. However, after 8 weeks, there was no significant difference in b-wave amplitude response between the inactive and active devices. At 8 weeks, there was a significantly greater number of photoreceptors remaining for rats who had received either the ASR or inactive device compared with those rats that had undergone sham surgery or no surgery. Pardue and colleagues suggest that enhanced protective effects from the ASR may be possible by altering the design to increase current levels or by increasing environmental light levels to produce higher stimulation levels [54]. MPDA project

After collaborating with the Optobionics group between 1994 and 1995 [55], a Southern German team led by the University Eye Hospital in Tübingen, was formed in 1995 to develop a subretinal prosthesis. In 1996, the Institute of Micro-Electronics in Stuttgart developed a prototype microphotodiode array (MPDA) containing 7600 microelectrodes on a 3-mm disc, 50 µm in diameter [56]. In vitro techniques have been predominantly reported by the German subretinal project. The first generation of MPDAs were tested using a sandwich technique, which involved the retinae from newly hatched chickens being adhered to a recording multielectrode array (the ganglion cell side was adhered). The photoreceptor outer segments were then damaged and an MPDA placed onto the retina. This technique allowed the recording of stimuli from the MPDA [56]. A later study examined degenerated rat retinae [57]. The retinae were removed and cut into 5 × 5 mm segments, then attached to a 60-electrode microelectrode array. Beams of white light were flashed onto the MPDA and it was found that intrinsic ganglion cell activity could be recorded even with a highly degenerated retinal network. Further experiments have demonstrated that it should be possible to transform the basic features of images, such as points, bars and edges into

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activity of the existing retinal network; which suggests that shape perception and object location may be possible with a subretinal device [58]. However, recent epiretinal results from Rizzo and colleagues have not confirmed the pattern perception of phosphenes from patterned electrical stimulation of the retina [59]. Further tests have been conducted in order to test the biocompatibility stability of the MPDA. Various materials were placed in Petri dishes with the retinae of pigmented rats. For comparison, a control dish containing only the retinae and solution was used. None of the MPDA materials demonstrated a toxic effect. Retinal cell cultures from rats were also used by Guenther and colleagues to screen for technical implant material [60]. Although most materials (including iridium and silica) showed good biocompatibility, a reduced biocompatibility was found for titanium materials. Interestingly, a later paper by Hammerle and colleagues found that titanium nitrate had excellent biostability, both in vivo and in vitro [61]. Similarly to the Optobionics research, electroretinography was performed in rabbits and rats in order to measure the effectiveness of the MPDA. As the MPDA are sensitive to infrared light, it is possible to stimulate the retina and measure the current discharged from the MPDA. This method should be useful for the localizing electrical responses from an MPDA. As with the early Optobionics MPDA [49], Zrenner and colleagues found in their early work that metabolic processes in the photoreceptor layer can be disrupted by the MPDA and they placed very thin holes in their device to allow nutrients to be passed [56]. As natural photoreceptors are far more efficient than photodiodes, visible light is not powerful enough to stimulate the MPDA. Therefore, infrared enhancement of the photodiode arrays (by inserting an additional layer in the array) has been suggested to enhance the stimulation current [43]. The German team commenced in vivo experiments in 2000, when evoked cortical potentials were measured from Yucantan micropigs and rabbits. The micropigs have eyes which are comparable in size and function with human eyes [62]. At 14 months post implantation, the implant and retina surrounding it were examined and there were no noticeable changes to anatomical integrity [63]. However, because the existing MPDA does not function in ambient light conditions, an electrode foil prototype with similar properties was implanted. The micropigs required a higher threshold level than the rabbits [64], however, the implants were successful in producing evoked cortical potentials in half of the animals tested. The thresholds identified in this study were similar to those required in epiretinal stimulation [64]. The latest reports from this group concern the results of in vivo experiments in cats. Volker and colleagues described the use of optical coherence tomography to examine the morphologic and circulatory conditions of the cat neuroretina and it’s interface with an implanted MPDA [65].

neurons onto electrodes and then guiding the axons towards the CNS. As this hybrid retinal implant will not require retinal ganglion cells or an optic nerve, it could be useful for patients with diseases in these components of the visual pathway. Results of an experiment with neural cells obtained from the spinal cords of a 3–4- week-old rat are described by Ito and colleagues [66]. Another study by this team investigated electrical stimulation requirements by stimulating the lateral geniculate nucleus in a cat. Recordings of the evoked potentials from the cat’s cortex found that pulse amplitude was a more important factor than pulse duration and that a biphasic pulse pattern was the most effective stimulation pattern [67]. Further studies have suggested using a computer model for the 3D configuration of electrode arrays [68]. Peterman and colleagues are also investigating the use of directed cell growth and localized neurotransmitter release for a retinal interface. They have been successful in directing the growth of neurons in a defined direction, using micropatterned substrates [69] and have demonstrated that the localized chemical stimulation of excitable cells is feasible. The authors suggest that chemical stimulation can have a similar spatial resolution as an electrical stimulation but with the ability to mimic the major functions of synaptic transmission [70]. An interesting design for a MPDA has been recently reported by Ziegler and colleagues, who propose a device where each pixel acts as an independent oscillator whose frequency is controlled by light intensity [71]. Kanda has suggested an alternative stimulation method for a retinal device: suprachoroidal-transretinal stimulation (STS), which does not involve the attachment of electrodes to the retina [72]. This should result in less complicated surgery for blind patients. The anodic-stimulating electrode is located on the choroidal membrane and the cathode is located in the vitreous body. This technique has been used in animal experiments where evoked potentials were recorded from the superior colliculus in rats. The authors are planning long-term, in vivo biocompatability studies [72]. However, it has been demonstrated that neural cells should not be separated from electrodes by more than a few µm, due to overheating, crosstalk between neighboring pixels and electrochemical erosion [73]. The thickness of the choroid is approximately 400 µm, therefore, suprachoroidal placement precludes close proximity between electrodes and cells, which will limit the potential visual acuity of the STS approach. Epiretinal stimulation

An epiretinal device involves a neurostimulator chip being implanted against the ganglion cells in the retina. This approach attempts to stimulate the remaining retinal neurons of patients who are blind from end-stage photoreceptor diseases. Retinal implant

Other subretinal methods

A team of Japanese researchers, led by Tohru Yagi of Nagoya University has been investigating the attachment of cultured

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Formerly from the Wilmer Ophthalmological Institute, John Hopkins Hospital, Mark Humayun and Eugene De Juan Jr are currently based at the Doheny Retina Institute at the University



of Southern California (CA, USA). Humayun’s PhD thesis demonstrated that a visually impaired person could perceive phosphenes during stimulation of the retina [74]. The engineering aspects of developing electronic stimulators and supporting electronics have been mainly conducted by Wentai Liu and his team at North Carolina State University [75]. In the first experiment to demonstrate successful phosphene perception from local electrical stimulation of the retina, 14 patients (12 with RP, and two with age-related macular degeneration) had their inner retinal surface electrically stimulated under local anaesthesia [76]. The responses were retinotopically correct in 13 of the patients, with the remaining patient, blind from birth, unable to distinguish anything apart from flashing light. The phosphenes were perceived exactly with the timing of the electrical stimulation [76]. Flicker fusion was tested in two subjects and found to occur at approximately 50 Hz; the phosphenes also appeared brighter at higher frequency [77]. An earlier paper also reported on five of these patients [78]. In 1999, a further experiment was reported on nine subjects, involving nine or 25 electrode array electrodes [45]. The electrodes were placed against the retinal surface and handheld in place using a silicon-coated cable with the guidance of a surgical microscope. The flicker fusion frequency was found to be 50 Hz in two subjects and 40 Hz in another two subjects (the remaining subjects were not tested). By scanning with the headmounted camera, subjects were able to perceive simple shapes in response to stimulation (e.g., horizontal and vertical lines and ‘U’ and ‘H’ shapes). A report on the long-term biocompatibility of an implanted, inactive epiretinal device was also published in 1999 [79], in which 25 platinum disc-shaped electrodes in a silicon matrix were implanted into the retinal surface of four normally sighted dogs. The arrays were held in place using metal alloy tacks. Over a 6-month period the implants were biologically tolerated well, mechanically stable and could be securely attached to the retinal surface [79]. A design for a functioning retinal prosthesis system has been described in joint papers by Liu and colleagues at North Carolina State University and the John Hopkins team in 1999 [80,81]. The proposed device, termed the multiple unit artificial retina chipset (MARC), consists of the extraocular unit containing the video camera and video processing board, connected by a telemetric inductive link to the intraocular unit. The power and signal transceiver, stimulation driver and electrode array are contained in the intraocular unit. In 2003, after obtaining FDA approval, the Doheny Eye Institute team and Second Sight (CA, USA), a company formed by former North Carolina State University team member, Robert Greenberg and Alfred Mann, developed the first human epiretinal implant. A subject with advanced RP received an implanted 4 × 4-electrode array, connected by a subcutaneous cable to an extraocular unit which was surgically attached to the temporal area of the skull. A wireless link transferred data and power from a belt-worn visual-


processing unit to the extraocular unit. All 16 electrodes produced phosphenes and the subject was able to detect ambient light, motion and correctly recognize the location of phosphenes (e.g., left vs. right or upsidedown). Future plans are to develop more complex stimulation control and provide a higher number of electrodes [82]. The use of microwire glass is also being investigated as a method to assist with the mapping of flat microelectric stimulator chips and curved neuronal tissue [83]. Retinal prosthesis project

Following earlier collaborative work with Humayan and deJuan, Wentai Liu and his team have continued with the development of an epiretinal prosthesis. A 60-electrode stimulating chip, which integrates power transfer and back telemetry, has been developed [84]. One of the advantages of this system would be removing the requirement for the cable connecting the intraocular and extraocular units described in the Doheny Eye Institute team implant [82]. Second Sight

Second Sight is a company formed by Robert Greenberg (from the Retinal Prosthesis Project led by Wentai Lui) and Alfred Mann (also the founder of the Cochlear Implant company Advanced Bionics). Second Sight developed the epiretinal device implanted into a blind patient by the Doheny Eye Institute team, as described previously [82]. Boston retinal implant project

This project is a collaboration between Joseph Rizzo (Massachusetts Eye and Ear Infirmary, Harvard Medical School, MA, USA) and John Wyatt (Massachusetts Institute of Technology, MA, USA) to develop an epiretinal prosthesis. The main difference between their approach and Humayun and colleagues, is the use of a miniature laser, located in a pair of glasses, to transfer power and data to a stimulator chip. Although the laser is required to be accurately directed to the implant and needs to cope with blinking, it will not be effected by electronic noise interference (unlike radiofrequency transmission) [85]. Electrically invoked cortical potentials have been successfully recorded from stimulation of a rabbit retina [86]. Recently, the microelectrode arrays have been tested with six patients, five of them legally blind from RP. The sixth patient was normally sighted, however their eye required removal due to orbital cancer. All patients were able to perceive phosphenes in response to stimulation, however, the results were mixed. Threshold charge densities were found to be significantly higher and above safe levels, in blind patients compared with the normally sighted patient [59]. In this study, it was often found that multiple phosphenes would be presented when a single electrode was stimulated, for example, 60% of tests in one subject. In addition, multiple-electrode stimulation did not reliably produce matching phosphenes [87].

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EPI-RET

Rolf Eckmillar from the University of Bonn (Germany), leads the German EPI-RET project, which involves 14 research groups. The aim of their first epiretinal device is to allow blind people to identify the location and shape of large objects [88]. Their approach involves replicating a healthy retina with a retinal encoder device, which consists of a photosensor array of 10,000–100,000 pixel inputs and simulated output of 100–1000 ganglion cells. Eventually, this project aims to embed this encoder into a contact lens. The output from the encoder is then sent to an implanted retinal stimulator. Eckmilliar and colleagues suggest that a future epiretinal prosthesis will be tuned (to optimize phosphene perception) during a dialog between a subject and their retinal encoder [89–92]. More recently, a learning active vision encoder (LAVIE) has been proposed to compensate for spontaneous eye (drift or nystagmus) and head movements in the absence of vision. A smooth pursuit function is also being investigated [93]. Flat platinum microelectrodes have been developed for the EPI-RET project and evoked cortical potentials have been recorded after stimulation in rabbits [94]. In 2000, Hesse and colleagues reported problems with the fixation of the electrode film and the retina in a cat experiment, partly due to the very thin posterior sclera [95]. Research into alternate electrode shape and fixation techniques is planned. The company Intelligent Implants was formed in 1998 to commercialize research by the EPI-RET group [93].

Microsystems-Based Visual Prosthesis & OPTIVIP projects (ESPRIT programme of the European Union)

The Microsystems-Based Visual Prosthesis (MiVip) team, led by Claude Veraat of the Neural Rehabilitation Engineering Laboratory, Université Catholique de Louvain in Belgium, has developed a prosthesis system which includes a spiral cuff silicon electrode to stimulate the optic nerve. In February 1998, a 59-year-old blind patient was implanted with the optic nerve visual prosthesis. Localized phosphenes were successfully produced throughout the visual field and changing pulse duration or amplitude could alter their brightness. After training it was reported that the patient could perceive different shapes, line orientations and even letters [102]. However, this system only displays one phosphene at a time and pattern recognition was achieved by the subject scanning with a head-mounted camera over a time period of up to 3 min. An interesting feature of this study has been the different phosphene shapes that have been generated; if these could be reliably replicated they might add a useful dimension to prosthetic vision. The cuff electrode consists of four platinum contacts and is able to adapt continuously to the diameter of the optic nerve. Initially a subcutaneous connector conducted stimulation of the electrode, however, in August 2000, a neurostimulator and antenna were implanted and connected to the electrode. An external controller with telemetry was then used for stimulating the cuff electrode. Recently, an adaptive neural network technique has been proposed to classify the phosphenes generated by this device [103,104].

University of NSW and University of Newcastle Vision Prosthesis Project

AHV simulation studies

Australian research on an epiretinal prosthetic vision system is occurring at the Vision Prosthesis Project at the Universities of NSW and Newcastle, led by Gregg Suaning and Nigel Lovell. This project aims to extend concepts from the development of cochlear prostheses. A 100-channel neurostimulator circuit for the retina has been developed, which uses bidirectional radiofrequency telemetry for transferring data and power [16,44]. A data format protocol has been introduced. The 100-channel neurostimulator was found to function and successfully produce evoked potentials in sheep [96–98]. An inexpensive technique for manufacturing platinum spherical electrodes has also been proposed [99]. Recently, an hexagonal mosaic of intraocular electrodes has been suggested by Hallum and colleagues to optimize the placement of electrodes and therefore improve visual acuity in prosthesis patients [100]. A prototype for an epiretinal system, capable of 840 stimulating events per second, using this electrode placement combined with a filtering approach to image processing, has also been described [101].

Due to the difficulty in obtaining experimental participants with an AHV device implanted, a number of simulation studies have been conducted with normally sighted subjects. However the simulation approach assumes that normally sighted people are receiving the same experience as a blind recipient of an AHV system. Weiland and Humayun have stated that human implant studies are the only method of verifying the effectiveness of a visual prosthesis and have questioned the validity of simulation studies [105]. A frequently cited prosthetic vision simulation was conducted in 1992 at the University of Utah by Cha and colleagues, in order to calculate the minimum number of phosphenes required for adequate mobility [106]. The pixelized vision simulator device consisted of a video camera connected to a monitor in front of the subject’s eyes. A perforated mask was placed on the monitor to reproduce the effect of individual phosphenes. The artificial environment consisted of an indoor maze, which contained paper column obstacles. Walking speed and frequency of contact were used as dependant variables. This research found that a 25 × 25 array of phosphenes, with a field of view of 30° would be required for a successful device. The simulation display employed by Cha and colleagues used a simple television-like display. Hayes and colleagues have described a more sophisticated approach [107], in which two different image-processing applications were used to display

Optic nerve devices

The optic nerve is a collection of 1 million individual fibers running from the retina to the lateral geniculate body. This nerve can be reached surgically and could provide a suitable location for implanting a stimulation electrode array.

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simulated phosphenes to a seated subject, who wore a headmounted display. The first image processing application used a simple square phosphene array, where each phosphene consisted of a solid grey scale value equal to the mean luminance of the contributing image pixels. The second image processing application used a Gaussian filter. Array size, contrast level, dropout percentage, simulated phosphene size and background noise were adjustable features of the simulation. Object recognition (including plate, cup and spoon), reading, candy pouring and cutting accuracy tasks were conducted under different simulation conditions. The main result was to conclude that the phosphene array size would be the most important factor in a useable prosthesis. Another image processing approach investigated the requirements for AHV facial recognition in [108]. A low vision enhancement system connected to a PC and driven by a visual basic program was used to display the images. Subjects were required to select which simulation image best matched a set of four normal images of human faces (the images of the same person were varied by head angle and whether the person was smiling or serious). All images displayed occupied a visual field of 13° horizontally and 17° vertically. The simulation display was presented in a circular dot mask, rather than the contiguous square blocks. Electrode properties (such as dropouts; size and gaps), contrast and grey levels could be varied experimentally. The grid sizes used in this study varied from 10 × 10 to 32 × 32 phosphenes. The authors found high accuracy for all high contrast tests (except those with significant dropout and two gray levels) and suggest that reliable face recognition using a crude pixelized grid is feasible. Research at the Queensland University of Technology (Australia), has examined the use of various image-processing techniques (such as enhancing edges, using different grey scales and extracting the most important image features) to identify a recognition threshold for low-quality stationary images [109]. These images are used to represent the limited number of phosphenes available to the subject (typically a 25 × 25 array). This research has found that at these low information levels the use of image- processing techniques is not helpful in the identification of static scenes, although an automatic zoom feature did aid image understanding. Additional research at Queensland University of Technology is investigating methods for the assessment and enhancement of mobility for AHV system users [110]. Expert opinion

With our current understanding of neuronal mechanisms in the visual system, AHV systems do not appear likely to replace the functioning of normal human vision. It is not likely that a regularly organized array of phosphenes will occur as a result of current technology microelectrodes [21]. While the development of AHV systems continues, research into retinal transplantation, growth factors and gene therapy has commenced which may also provide alternative treatment options for blindness.


AHV systems are likely to offer benefits in the areas of mobility and reading. An important question is whether the benefits from these systems are worth the cost. Despite the overloading of another sensory input channel, traditional mobility aids and ETA devices (such as the vOICe system from Peter Meijer [201]), are probably cheaper, less invasive and may require a similar amount of training to AHV systems. Additionally, most people who are classified as blind are elderly and still have some remaining vision, and therefore are probably not suited to an AHV system. The need for standard psychophysical assessment methods have been noted by a number of AHV researchers [101,111]. To inform consumers on the benefits of an AHV system compared with other technical aids for the blind, future research comparing the effectiveness of these devices would be useful. The lack of a method to compare mobility has also been raised by Dobelle [13]. However, there are a number of mobility assessment methods presented in the Orientation and Mobility Literature which could be useful for comparison of AHV systems and other devices [112–114]. AHV research offers important insight regarding the functioning of the human visual system and in brain-computer interface technology. The subretinal device from Optobionics has shown impressive results, however, these results may be due to neurotrophic effects rather than the microphotodiode implant used. Current research in other AHV systems is promising, however, there appears to be significant development required before they can provide useful mobility and reading. Excellent additional review papers on AHV include [38,50,115,116]. Five-year view

The subretinal implants demonstrate the greatest promise in restoring some vision, however, there are doubts over whether the improvements in vision are due to neurotrophic effects or the device itself. Further tests to determine the reason for the improvements are planned. If the device is responsible, it is conceivable to see these implants available in the next 5 years. The cortical implant system from the Dobelle institute is commercially available; however it has not been approved by the FDA. A 5-year view on this system is not possible, as information regarding the system and patient outcomes are not made public. A recent article in the Wall Street Journal [117] reported a 33-year-old female recipient who paid US$100,000 for the Dobelle system and was only able to use it for 15 min per day (as it was tiring and caused head pain). The remaining cortical and optic nerve systems are still in varying stages of preliminary human or animal testing. Preliminary research has also commenced on microstimulation of the lateral geniculate nucleus [118]. Although progress will be made, it does not appear likely that a commercial system using these methods will be available in the next 5 years. Acknowledgements

This research was supported by Cochlear Ltd and the Australian Research Council through ARC Linkage Grant project 0234229.

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Information resources

Main contacts and project websites: • Bionic Eye Research Project (Cortical Neuroprosthesis, University of New South Wales, Australia) Vivek Chowdhury and John Morley http://ophthalmology.med.unsw.edu.au/bioniceye.htm • Cortical Implant for the Blind (CORTIVIS, Europe) Edwardo Fernandez http://cortivis.umh.es/ • EPI-RET (Retina implant research in Cologne, Germany) Rolf Eckmiller www.medizin.uni-koeln.de/kliniken/augenklinik/epiret3e.htm • Intracortical visual prosthesis (Illinois Institute of Technology) Phillip Troyk http://neural.iit.edu/intro.html • Microsystems-Based Visual Prosthesis (MiVip, ESPRIT program of the European Union, now OPTIVIP) Claude Veraart www.md.ucl.ac.be/gren/Projets/mivip.html • OPTIVIP projects (ESPRIT program of the EU) Claude Veraart www.dice.ucl.ac.be/optivip/ • Optobionics Corporation (USA) Alan Chow and Vincent Chow www.optobionics.com • Retinal Implant (Doheny Retina Institute, University of Southern California, USA) Mark Humayun and Eujene De Juan Jr www.usc.edu/hsc/doheny/ • Retinal Implant & Biohybrid Implant (Japan) Tohru Yagi www.bmc.riken.jp/~ yagi/retina/ • Retinal Implant-AG (was SUB-RET project, Germany) Eberhart Zrenner www.retina-implant.de/tour/ • Retinal Prosthesis Project (North Carolina State University) Wentai Liu www.icat.ncsu.edu/projects/retina/ References 1

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Affiliation •


Meijer PBL. Vision technology for the totally blind (2003). www.seeingwithsound.com/ (Accessed December, 2004)

Jason Dowling Queensland University of Technology, School of Electrical and Electronic Systems Engineering, Faculty of Built Environment and Engineering,, Brisbane, Australia Tel.: +617 3864 1608 Fax: +617 3864 1516 [email protected]

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