**Abstract**

The field of retinal prosthetics has seen significant advances in the past 3 decades. Encouraging results from different groups have shown coarse objective functional improvement, using a range of technological and surgical approaches. The Argus II retinal prosthesis system was the first of its kind to receive regulatory approval for commercial use in Europe and the USA. The device is designed to replicate the function of photoreceptors in converting visual information into electrical neural signals in patients with profound visual loss secondary to degenerative retinal disease. Results from a phase II study of 30 patients have demonstrated improved performance in basic tests of visual function, object recognition, letter reading, prehension, orientation and mobility tasks. It is now the most widely implanted retinal prosthetic device worldwide. This chapter provides an overview of the requirements of a retinal prosthetic system, the results from the Argus II device to date, and an insight into some of the challenges and future directions of visually restorative therapies.

**Keywords:** retinal prosthesis, Argus II, artificial vision

#### **1. Introduction**

Retinal diseases, including both inherited and acquired conditions, are a major cause of blindness. In 2010, the WHO estimated that 285 million people in the world were visually impaired from all causes [1]. Hereditary retinal disease represents another significant contributor to unavoidable worldwide blindness, with conditions such as retinitis pigmentosa (RP) affecting an estimated 1/4000 people, or 0.025% of the population, often of working age [2]. Representing a heterogenous group of inherited diseases, RP affects the rod and cone photoreceptors (PRs), causing progressive, profound visual impairment, but with relative preservation of the inner retinal architecture [3]. This anatomical region consists of retinal ganglion cells (RGCs) and their nerve axons, which transmit visual information to the brain, along with other regulatory interneurons, such as bipolar, amacrine and horizontal cells, and Müller support cells (**Figure 1**). Preservation of these structures and the associated retinotopic map has led to RP becoming a model for many forms of visual restorative therapy, in particular, retinal prosthetics.

Another significant retinal cause of blindness is age-related macular degeneration (AMD), accounting for 5% globally [1]. It has been projected that, by 2040, this condition alone will affect 288 million people, 3.25% of the predicted global population [4, 5]. Late AMD comprises geographic atrophy (dry) and neovascular (wet) AMD, and is a significant cause of morbidity in the western world, with a

#### **Figure 1.**

*A schematic demonstrating the anatomy of the eye and organization of the retina. RNFL: retinal nerve fibre layer; RGCs: retinal ganglion cells; RPE: retinal pigment epithelium.*

prevalence of 2.4% in the UK [6, 7]. While anti-VEGF treatment has revolutionized the treatment of wet AMD, there is currently no treatment for the dry subtype, which results in degeneration of the PR layer and impairment of central vision in 1.3% of the UK population [7].

The concept of retinal prosthetics is centred on the phenomenon of electrically induced subjective visual percepts or 'phosphenes'. These phosphenes have been elicited by applying electrical currents across the ocular surface since as long ago as the eighteenth century. In the early twentieth century, Förster demonstrated that phosphenes could be elicited in blind patients via direct stimulation of the visual cortex, leading, in 1968, to the first chronic implantation of an intracranial visual prosthesis [8, 9]. In the 1980s, advances in microfabrication, materials engineering and retinal surgery provided a fecund environment for emergence of the field of retinal prosthetics—devices that could deliver direct stimulation to the residual retinal neurons.

#### **2. Principles of natural vision**

In order to create a *retinal* prosthesis, it is necessary to account for the processes that take place within the human eye, where light is absorbed, converted to an electrical impulse and encoded into a neural signal. Physiological capture of the visual scene occurs via the natural optical system, comprising the cornea, iris and crystalline lens, which focus light onto the photosensitive retinal cells. Within the photosensitive rods and cones, a photochemical reaction leads to transduction of light into a graded electrical neural signal with eventual RGC stimulation. The axons of the RGCs constitute the optic nerve. In the native retina, a significant amount of information compression occurs at the level the PRs, the interneurons and the RGCs, from where it is encoded for transmission via the optic nerve to the midbrain and cortical visual pathways.

There are two types of PR, rod and cone cells, which number ~120 and 6 million respectively in each eye, resulting in an average input of 100 photoreceptors to each of 1.5 million RGCs [10, 11]. Rods are sensitive to low levels of light and are most

**91**

*The Argus II Retinal Prosthesis System*

considerably in density [12].

takes place [12].

amount of visual information.

functional value [18, 19].

*DOI: http://dx.doi.org/10.5772/intechopen.84947*

populous at about 20° eccentricity. The cone cells are responsible for colour vision and function best in bright light. They are most densely concentrated in the foveal region where they are in almost 1:1 ratio with RGCs, beyond which they decline

Following the transduction of photic energy into electrical impulses, bipolar cells effectively transmit the information from PRs to RGCs, but may have an excitatory (ON) or inhibitory (OFF) response to hyperpolarisation and are also influenced by the actions of horizontal and amacrine cells, which can introduce lateral inhibition of signals. Each RGC has a centre-surround receptive field organization and its stimulation pattern will depend both on the size of its receptive field, the input stimulation frequency, and whether it is an 'on-centre' or 'off-centre' cell. Furthermore, RGCs are not functionally homogeneous, with certain cell populations specialized in particular functions and projecting to specific midbrain regions. Most of the 1 million nerve axons of the RGCs pass via the optic nerve to their respective lateral geniculate nucleus (LGN), located within the thalamus. The LGN is a layered structure and each part receives axons from specific ganglion cell types. A degree of visual processing is thought to occur at this point, before projecting on towards the primary visual cortex, where all higher cognitive processing

The processing power of the retina enables us to resolve detail with remarkably high spatial and temporal resolution, across a broad spectrum of contrast and colour. Beyond this, higher neuro-cortical integration allows us to process and recognize objects, words and faces, appreciate distance, orientation and movement, while coordinating our visual interpretations with other sensory inputs and motor outputs. Together this information allows us to decide what is safe or dangerous, fast or slow, attractive or repulsive. All this activity occurs in milliseconds, with a seemingly infinite refresh rate. This phenomenon is reliant on a very complex system that can rapidly capture, assimilate, compress and process an enormous

Clearly, creating a micro-electronic system, which can come close to replicating the processing capacity of the human visual system, is currently an unrealistic goal. Instead, we must focus on how visual processing software and hardware engineering can be combined to produce a device that can resolve the minimum interpretable visual information such as to be beneficial to patients with profound vision loss. Simulated prosthetic vision (SPV) studies have been undertaken to try and estimate the optimum spatiotemporal image processing techniques for specific task completion, as well as the basic hardware requirements to best deliver RGC stimulation patterns [13–17]. SPV studies have extensively investigated the spatial resolution, visual field and contrast required for assorted activities of daily living, concluding that a minimum resolution of ~600–1000 pixels over a visual field 15° × 15° can permit reasonable accuracy in manipulation, recognition, orientation

some currently available photovoltaic retinal prosthetic systems while fields of at least 15° × 15° have been created. However, and disappointingly, there remains a mismatch in the functional aptitude demonstrated by subjects in SPV studies and that in recipients of visual prostheses. This suggests that other factors, such as the effects of behavioural adaptation, perceptual learning and cortical plasticity, as well as the loss of the intrinsic retinal processing capacity, could be critical requisites in the development of a visual restorative system that could deliver appreciable

One of the advantages of a *retinal* prosthesis is that, by placing a device at the most distal part of a non-functioning visual system, it is possible to benefit from any residual downstream neuronal organization within the retina and visual

is similar to that in

and mobility tasks. The resolution of around 3 pixels/degree2

#### *The Argus II Retinal Prosthesis System DOI: http://dx.doi.org/10.5772/intechopen.84947*

*Prosthesis*

**Figure 1.**

1.3% of the UK population [7].

*layer; RGCs: retinal ganglion cells; RPE: retinal pigment epithelium.*

**2. Principles of natural vision**

midbrain and cortical visual pathways.

retinal neurons.

prevalence of 2.4% in the UK [6, 7]. While anti-VEGF treatment has revolutionized the treatment of wet AMD, there is currently no treatment for the dry subtype, which results in degeneration of the PR layer and impairment of central vision in

*A schematic demonstrating the anatomy of the eye and organization of the retina. RNFL: retinal nerve fibre* 

The concept of retinal prosthetics is centred on the phenomenon of electrically induced subjective visual percepts or 'phosphenes'. These phosphenes have been elicited by applying electrical currents across the ocular surface since as long ago as the eighteenth century. In the early twentieth century, Förster demonstrated that phosphenes could be elicited in blind patients via direct stimulation of the visual cortex, leading, in 1968, to the first chronic implantation of an intracranial visual prosthesis [8, 9]. In the 1980s, advances in microfabrication, materials engineering and retinal surgery provided a fecund environment for emergence of the field of retinal prosthetics—devices that could deliver direct stimulation to the residual

In order to create a *retinal* prosthesis, it is necessary to account for the processes

There are two types of PR, rod and cone cells, which number ~120 and 6 million respectively in each eye, resulting in an average input of 100 photoreceptors to each of 1.5 million RGCs [10, 11]. Rods are sensitive to low levels of light and are most

that take place within the human eye, where light is absorbed, converted to an electrical impulse and encoded into a neural signal. Physiological capture of the visual scene occurs via the natural optical system, comprising the cornea, iris and crystalline lens, which focus light onto the photosensitive retinal cells. Within the photosensitive rods and cones, a photochemical reaction leads to transduction of light into a graded electrical neural signal with eventual RGC stimulation. The axons of the RGCs constitute the optic nerve. In the native retina, a significant amount of information compression occurs at the level the PRs, the interneurons and the RGCs, from where it is encoded for transmission via the optic nerve to the

**90**

populous at about 20° eccentricity. The cone cells are responsible for colour vision and function best in bright light. They are most densely concentrated in the foveal region where they are in almost 1:1 ratio with RGCs, beyond which they decline considerably in density [12].

Following the transduction of photic energy into electrical impulses, bipolar cells effectively transmit the information from PRs to RGCs, but may have an excitatory (ON) or inhibitory (OFF) response to hyperpolarisation and are also influenced by the actions of horizontal and amacrine cells, which can introduce lateral inhibition of signals. Each RGC has a centre-surround receptive field organization and its stimulation pattern will depend both on the size of its receptive field, the input stimulation frequency, and whether it is an 'on-centre' or 'off-centre' cell. Furthermore, RGCs are not functionally homogeneous, with certain cell populations specialized in particular functions and projecting to specific midbrain regions. Most of the 1 million nerve axons of the RGCs pass via the optic nerve to their respective lateral geniculate nucleus (LGN), located within the thalamus. The LGN is a layered structure and each part receives axons from specific ganglion cell types. A degree of visual processing is thought to occur at this point, before projecting on towards the primary visual cortex, where all higher cognitive processing takes place [12].

The processing power of the retina enables us to resolve detail with remarkably high spatial and temporal resolution, across a broad spectrum of contrast and colour. Beyond this, higher neuro-cortical integration allows us to process and recognize objects, words and faces, appreciate distance, orientation and movement, while coordinating our visual interpretations with other sensory inputs and motor outputs. Together this information allows us to decide what is safe or dangerous, fast or slow, attractive or repulsive. All this activity occurs in milliseconds, with a seemingly infinite refresh rate. This phenomenon is reliant on a very complex system that can rapidly capture, assimilate, compress and process an enormous amount of visual information.

Clearly, creating a micro-electronic system, which can come close to replicating the processing capacity of the human visual system, is currently an unrealistic goal. Instead, we must focus on how visual processing software and hardware engineering can be combined to produce a device that can resolve the minimum interpretable visual information such as to be beneficial to patients with profound vision loss.

Simulated prosthetic vision (SPV) studies have been undertaken to try and estimate the optimum spatiotemporal image processing techniques for specific task completion, as well as the basic hardware requirements to best deliver RGC stimulation patterns [13–17]. SPV studies have extensively investigated the spatial resolution, visual field and contrast required for assorted activities of daily living, concluding that a minimum resolution of ~600–1000 pixels over a visual field 15° × 15° can permit reasonable accuracy in manipulation, recognition, orientation and mobility tasks. The resolution of around 3 pixels/degree2 is similar to that in some currently available photovoltaic retinal prosthetic systems while fields of at least 15° × 15° have been created. However, and disappointingly, there remains a mismatch in the functional aptitude demonstrated by subjects in SPV studies and that in recipients of visual prostheses. This suggests that other factors, such as the effects of behavioural adaptation, perceptual learning and cortical plasticity, as well as the loss of the intrinsic retinal processing capacity, could be critical requisites in the development of a visual restorative system that could deliver appreciable functional value [18, 19].

One of the advantages of a *retinal* prosthesis is that, by placing a device at the most distal part of a non-functioning visual system, it is possible to benefit from any residual downstream neuronal organization within the retina and visual

pathways. However this theory relies on the assumption that the proximal visual system remains intact. It has been demonstrated that outer retinal degenerative disease results in a cascade of reorganization and remodelling within the retina and central nervous system, even taking place before there is clinical evidence of PR loss [20–24]. A stepwise deterioration culminates in extensive neuronal cell migration, rewiring and death, accompanied by glial hypertrophy and retinal remodelling, rendering the retina incapable of processing or encoding visual data. This neuronal plasticity carries implications for all forms of visually restorative therapy, but particularly for prostheses, which are currently introduced at a late stage of visual impairment, where there has already been widespread reorganization with limited scope for rescuing vision. However, it may be that future iterations of bionic devices could even be introduced earlier in the disease process in an attempt to halt or reverse the remodelling process.

Another matter that remains unclear is the extent to which the human brain undergoes reorganization following loss of visual sensory input. Both animal and human studies have shown that there is the capacity for neuroplasticity as a functional adaptation to loss of a sensory modality [25–27]. For example, visual cortical activity has been demonstrated in blind subjects while reading Braille [28, 29]. Other studies of patients undergoing cochlear implant surgery, have shown correlation between the pre-operative auditory organization and activation and subsequent success of the neuroprosthesis [30, 31]. If a method could be developed by which a patient could be assessed for the feasibility of generating interpretable phosphenes, this would enhance patient selection and thus outcomes in this area of visual restoration. Further understanding of the nature of cortical plasticity in sensory loss and how subjects can adapt to a new form of vision with perceptual learning and rehabilitation, is sure to enhance the beneficial effect of visual restorative treatments in the future.
