Directed retinal nerve cell growth for use in a retinal prosthesis interface

PURPOSE: Retinal prosthetic devices that use microelectrode arrays to stimulate retinal nerve cells may provide a viable treatment for degenerative retinal diseases. Current devices are based on electrical field-effect stimulation of remaining functional neural elements. However, the distance between target neurons and electrodes limits the potential density of electrodes and the ability to stimulate specific types of retinal neurons that contribute to visual perceptions. This study was conducted to investigate the use of microcontact printing (muCP) to direct cultured or explant retinal ganglion cell (RGC) neurites to precise and close stimulation positions and to evaluate the cell types that grow from a retinal explant. METHODS: RGCs and whole retinal explants were isolated from postnatal day-7 Sprague-Dawley rats using immunopanning purification and microdissection, respectively. Aligned muCP was used to direct the growth of RGC neurites from pure cultures (n=105) and retinal explants (n=64) along laminin patterns and to individual microelectrodes. Immunofluorescence stains (n=39) were used to determine the cell types that grew out from the retinal explants. RESULTS: RGC neurite growth was directed reproducibly along aligned laminin micropatterns to individual microelectrodes in pure RGC cultures and from full-thickness explanted rat retinas in 92% of experiments, neurites from pure RGC cultures extended along the laminin lines with an average length of 263 +/- 118 microm (SD; n=27) after 24 hours. Neurites from retinal explants extended in more than 80% of experiments and were observed to grow to an average length of 279 +/- 78 microm (n=64) after 2 days in culture. These neurites grew up to 3 mm after 1 month of culture on the laminin micropatterns. Immunohistochemical stains demonstrated that extended processes from both RGCs and glial cells grew out of retinal explants onto stamped laminin lines. CONCLUSIONS: Using muCP to pattern surfaces with growth factors, individual neuronal processes from pure RGC culture and whole retinal explants can be directed to discrete sites on a microelectronic chip surface. By directing RGC neurite processes to specific sites, single cell stimulation becomes possible. This may allow discrete populations of retinal neurons to be addressed so that physiologic retinal processing of visual information can be achieved.     

Optical and neural resolution in peripheral vision.

Visual acuity along the horizontal meridian in the peripheral field of vision was determined at a photopic level in two normal subjects. Two types of sinusoidally modulated, monochromatic test patterns of high contrast were used. One was produced directly on the retina by an interferometric technique. The other type was imaged on the retina by the dioptric apparatus of the eye; the resulting image suffered ordinary optical image degradation. The results from the interferometric acuity determinations represent maximal neural discrimination across the visual field. Acuity decreases monotonically toward the periphery, from about 45 cycles per degree in the fovea, to about 0.8 at 80 degrees of eccentricity in the temporal field. The decline is well described by a second-degree polynomial. Acuity for test patterns imaged by the optics of the eye was consistently lower than interferometric acuity. The difference increases toward the periphery. It is attributable to effects of optical aberrations. The discrepancy between optical and neural resolving power on oblique incidence needs to be taken into account whenever results obtained with external, extra-axial stimuli are to be analyzed in terms of retinal architecture.     

Characterization of mouse cortical spatial vision

Little is known about the spatial vision of mice or of the role the visual cortex plays in mouse visual perception. In order to provide baseline information upon which to evaluate the spatial vision of experimentally and genetically altered mice, we used the visual water task to assess the contrast sensitivity and grating acuity of normal C57BL/6 mice. We then ablated striate cortex (V1) bilaterally and re-measured the same visual functions. Intact mice displayed an inverse "U"-shaped contrast sensitivity curve with a maximum sensitivity near 0.2 cycles/degree (c/d). Grating acuity, measured either by discriminating a sine-wave grating from an equiluminant gray, or vertical from horizontal sine wave gratings, was near 0.55 c/d. Grating acuity and contrast sensitivity were reduced significantly following aspiration of V1. The mouse visual system exhibits fundamental mammalian characteristics, including the feature that striate cortex is involved in processing visual information with the highest sensitivity and spatial frequency.     

Development and surgical implantation of a vision prosthesis model into the ovine eye

Purpose: A surgical technique was designed and tested to enable the implantation of an intraocular electrical retinal stimulator. Method: An inoperative perspex and silicone model was constructed to closely resemble the anticipated properties of the proposed visual prosthesis. The animal model chosen for these experiments was the sheep, because the dimensions of its ocular anatomy are approximately 30% larger than the human’s, being otherwise grossly similar. The surgical method involved transplanar port‐hole lensectomy and vitrectomy, insertion of the model implant through a limbal incision, and fixation of the perspex subunit close to the location of the native crystalline lens, by way of trans‐pars plana fixation sutures. Adequate preretinal positioning of the implant’s silicone extension was obtained by way of its inherent elastic recoil. Results: The procedure was performed without macroscopic evidence of undue surgical trauma. Conclusion: Although further long‐term experiments are required to fully assess the surgical procedure and biocompatibility of the implant, intraoperative assessment and postmortem computed tomographic imaging of the globe has confirmed the successful intraocular positioning and fixation of the implant.     

Latent/manifest latent nystagmus reversal using an ocular prosthesis. Implications for vision and ocular dominance

Latent/manifest latent nystagmus (LMLN) is a jerk nystagmus with a decreasing-velocity or linear slow phase whose fast phase is in the direction of the fixating eye. Change of the fixating eye by alternating tropias or cover will cause reversal of the LMLN to preserve this relationship. In the dark, where no fixation is possible, the fast phases of LMLN are in the direction of the intended fixating eye; actual visual input will override this effect of intention. A patient with persistent hyperplastic primary vitreous of the right eye, which was enucleated at age 9 due to glaucoma, had LMLN with fast phases to the left. His congenitally blind right eye was replaced with an ocular prosthesis whose movements were conjugate with his seeing eye. In the dark, we found that his LMLN spontaneously reversed as the normally fixating left eye became esotropic. Furthermore, as is the case with LMLN patients who have sight in both eyes, he was able to willfully reverse his LMLN in the dark by alternating his "fixating" eye. We conclude from these observations that the direction of LMLN is determined at a cortical level, is intimately related to the intended fixating eye and that eye "dominance" is predetermined and not altered by visual abnormalities, including blindness.     

Development of object vision in infants with permanent cortical visual impairment.

We examined 30 infants in whom cortical visual impairment was diagnosed during their first year of life to ascertain prognostic factors for the development of object vision, defined as the ability to recognize faces or hand-held toys. All patients were followed up for a minimum of 12 months. The most common causes of cortical visual impairment in the 30 infants were hydrocephalus in nine infants (30.0%), birth asphyxia or neonatal hypoxia in eight infants (26.7%), intracranial hemorrhage with or without hydrocephalus in seven infants (23.3%), and meningitis in five infants (16.7%). Lack of development of object vision was associated only with hypoxia (P = .013). Findings on ophthalmic examination, an abnormality in the visual pathway on computed tomographic or magnetic resonance scan, and seizures, hydrocephalus, intracranial hemorrhage, meningitis, cerebral palsy, developmental delay, prematurity, microcephaly, and hearing deficit, did not appear to be risk factors for the lack of development of object vision.     

A training sequence for low vision patients.

A structured training program for teaching low vision patients to efficiently use their optical aids for reading tasks is presented. The arguments for the use of this particular training sequence is supported through the sample patient histories. The training sequences can be developed in any low vision practice and the materials are readily available. The importance of training in a low vision program is emphasized.     

Clinical and physiological aspects of the cortical visual prosthesis

Physiological concepts and experimental evidence indicate the feasibility of developing an effective artificial visual system through direct stimulation of the visual cortex. The technical, medical and physiological aspects are reviewed.     

Functional and cortical adaptations to central vision loss

Age-related macular degeneration (AMD), affecting the retina, afflicts one out of ten people aged 80 years or older in the United States. AMD often results in vision loss to the central 15-20 deg of the visual field (i.e. central scotoma), and frequently afflicts both eyes. In most cases, when the central scotoma includes the fovea, patients will adopt an eccentric preferred retinal locus (PRL) for fixation. The onset of a central scotoma results in the absence of retinal inputs to corresponding regions of retinotopically mapped visual cortex. Animal studies have shown evidence for reorganization in adult mammals for such cortical areas following experimentally induced central scotomata. However, it is still unknown whether reorganization occurs in primary visual cortex (V1) of AMD patients. Nor is it known whether the adoption of a PRL corresponds to changes to the retinotopic mapping of V1. Two recent advances hold out the promise for addressing these issues and for contributing to the rehabilitation of AMD patients: improved methods for assessing visual function across the fields of AMD patients using the scanning laser ophthalmoscope, and the advent of brain-imaging methods for studying retinotopic mapping in humans. For the most part, specialists in these two areas come from different disciplines and communities, with few opportunities to interact. The purpose of this review is to summarize key findings on both the clinical and neuroscience issues related to questions about visual adaptation in AMD patients.     

The interface between ophthalmology and optometric vision therapy

Considerable disparity lies between ophthalmologic impressions of optometric vision therapy, and the reality of optometric vision therapy as practiced in the United States. The viewpoint shared by ophthalmology in particular, and the medical field in general, is one that is filtered through organizational policy statements and the isolated experiences of influential individual practitioners. This has resulted in a skewed portrayal of optometric vision therapy. The purpose of this paper is to present a balanced perspective on this subject, and one that should be of assistance in creating an interface between ophthalmology and optometry that better serves the public.     

Longitudinal quantitative assessment of vision function in children with cortical visual impairment.

PURPOSE: Cortical visual impairment (CVI) is bilateral visual impairment caused by damage to the posterior visual pathway, the visual cortex, or both. Current literature reports great variability in the prognosis of CVI. The purpose of this study was to evaluate change in vision function in children with CVI over time using a quantitative assessment method. METHODS: The visual acuity and contrast sensitivity of children with CVI were retrospectively assessed using the sweep visual evoked potential (VEP). Thirty-nine children participated in the visual acuity assessment and 34 of the 39 children participated in the contrast threshold assessment. At the time of the first VEP, the children ranged in age from 1 to 16 years (mean: 5.0 years). The time between measures ranged from 0.6 to 13.7 years (mean: 6.5 years). RESULTS: Forty-nine percent of the children studied showed significant improvement of visual acuity. The average improvement was 0.43 log unit (mean change: 20/205 to 20/76) in those who improved. The initial visual acuity was worse in those who improved compared with those who did not improve (p < 0.001). Forty-seven percent of the children studied showed significant improvement of contrast threshold. In those who improved, the average amount of improvement was 0.57 log unit (10 to 2.6% Michelson). The initial contrast threshold was significantly worse in those who improved compared with those who did not improve (p = 0.001). Also, the change in contrast threshold was related to age of the child (p = 0.017). CONCLUSIONS: Significant improvement in vision function can occur over time in children with CVI. In the present study, approximately 50% of the children improved and the remainder remained stable. No relation was found between etiology and improvement. Further investigation is warranted to better understand the prognosis for visual recovery in children with CVI.     

A vision care module within a prototype HMO.

The Health Maintenance Organization (HMO) concept is dedicated to the prevention of disease and disability. Organizations incorporating this concept must include vision care if complete service is to be offered. Described in this paper is one such HMO, Group Health Cooperative of Puget Sound, with details of the successful integration of optometric vision care into this medically oriented, multidisciplinary setting.     

Hyper-vision in a patient with central and paracentral vision loss reflects cortical reorganization

SM, a 21-year-old female, presents an extensive central scotoma (30 deg) with dense absolute scotoma (visual acuity = 10/100) in the macular area (10 deg) due to Stargardt's disease. We provide behavioral evidence of cortical plastic reorganization since the patient could perform several visual tasks with her poor-vision eyes better than controls, although high spatial frequency sensitivity and visual acuity are severely impaired. Between 2.5-deg and 12-deg eccentricities, SM presented (1) normal acuity for crowded letters, provided stimulus size is above acuity thresholds for single letters; (2) a two-fold sensitivity increase (d-prime) with respect to controls in a simple search task; and (3) largely above-threshold performance in a lexical decision task carried out randomly by controls. SM's hyper-vision may reflect a long-term sensory gain specific for unimpaired low spatial-frequency mechanisms, which may result from modifications in response properties due to practice-dependent changes in excitatory/inhibitory intracortical connections.     

A four mechanism model for threshold spatial vision.

Data on the threshold visibility of spatially localized, aperiodic patterns are used to derive the properties of a general model for threshold spatial vision. The model consists of four different size-tuned mechanisms centered at each eccentricity, each with a center-surround sensitivity profile described by the difference of two Gaussian functions. The two smaller mechanisms show relatively sustained temporal characteristics, while the larger two exhibit transient properties. All four mechanisms increase linearly in size with eccentricity. Mechanism responses are combined through spatial probability summation to predict visual thresholds. The model quantitatively predicts the spatial modulation transfer function (cosine grating thresholds) under both sustained and transient conditions with no free parameters.     

Rehabilitation of lost functional vision with the Argus II retinal prosthesis

The Argus II retinal prosthesis is the first commercially available device for restoration of vision in patients with Retinitis Pigmentosa or with similar retinal pathology who still have minimal residual native vision. The technology is able to restore vision with production of artificial visual percepts which usually are given adequate useful interpretation by the visual system in most implanted patients. The technology usually produces visual perception at the level of shape identification or better in some cases enabling in many less dependence on vision substitution devices and skills. There is no consensus among vision rehabilitation practitioners on single methods for assessments, outcome measures and training, yet there is constant progress in these areas of concern. Hence the current vision rehabilitation practice related to the implantation of the Argus II retinal prosthesis is a work in progress with many learning opportunities for all involved. All agree that implementation of this technology in clinical practice requires the combined work of a multi-disciplinary team which includes a specialized surgical team as well as a specialized rehabilitation team in order to obtain optimal results. Our own experience is presented in this paper and indicates so far that the Argus II technology is beneficial to patients and that it could be successfully managed within the Canadian heath care system.