Retinal Stimulation Research Articles

Transcutaneous Electrical Retinal Stimulation Therapy for Age-Related Macular Degeneration

This reports the preliminary outcome of a transpalpebral electrical retinal stimulation therapy for age-related macular degeneration (ARMD).Twenty-one patients consisting of 16 with wet-type (Group-W) and 5 with dry-type (Group-D) ARMD with a mean age of 73.9 ± 9.5 years (range 51 to 85 years) were recruited for this study. Transpalpebral electrical retinal stimulation (20 minutes, 800 μA) was applied on the patients 4 times per day for up to 1 month. The mean best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study [ETDRS] score) changed from 29.5±5.1 to 31.8±5.0 in Group-W and from 39.8±4.7 to 42.9±4.9 in Group-D. Neither ocular nor systemic adverse effects were observed with the exception of one patient who developed contact dermatitis. Due to several limitations such as lack of control, patients’ learning effect, etc, the efficacy of the therapy could not be drawn. This preliminary study, however, showed that the transpalpebral electrical retinal stimulation therapy can be non-invasively applied on wet-type ARMD patients.

124. Threshold of monochromatic luminous stimulation in retina of healthy and diabetic subjects

124. Threshold of monochromatic luminous stimulation in retina of healthy and diabetic subjects

Development of an extraocular retinal prosthesis: Evaluation of stimulation parameters in the cat

Electrical stimulation of the retina with extraocular electrodes is a new approach to developing a retinal prosthesis for blind patients. We have evaluated stimulus and electrode configurations for an extraocular retinal prosthesis (ERP). In anesthetized cats, ERP disc electrodes of 1 mm, 2 mm and 3 mm diameter were sutured to the sclera over the lateral globe. Electrically evoked potentials (EEPs) were recorded over the ipsilateral visual cortex, which resulted from the retinal stimulation of the ERP electrodes with a return electrode placed at the medial canthus. Square pulses, triangular pulses and the effects of dark adaptation and electrode size on the amplitude and thresholds for a cortical response were investigated. Square pulses were more effective than triangular pulses for stimulating the retina. Dark adaptation leads to a large increase in the threshold for retinal stimulation. There was no difference in the threshold for stimulation between electrodes of 1 mm and 3 mm diameter. Stimulation of the retina with extraocular electrodes elicits an EEP that is similar to that generated by retinal stimulation with intraocular electrodes. The use of square pulses is preferred to triangular pulses to minimize the peak current density at the electrode–tissue interface. As there is little difference in the threshold current for retinal stimulation with 1 mm or 3 mm electrodes, 3 mm electrodes are preferred as this will decrease the charge density at the active surface of the electrode.

High-Resolution Electrical Stimulation of Primate Retina for Epiretinal Implant Design

The development of retinal implants for the blind depends crucially on understanding how neurons in the retina respond to electrical stimulation. This study used multielectrode arrays to stimulate ganglion cells in the peripheral macaque retina, which is very similar to the human retina. Analysis was restricted to parasol cells, which form one of the major high-resolution visual pathways in primates. Individual cells were characterized using visual stimuli, and subsequently targeted for electrical stimulation using electrodes 9-15 microm in diameter. Results were accumulated across 16 ON and 9 OFF parasol cells. At threshold, all cells responded to biphasic electrical pulses 0.05-0.1 ms in duration by firing a single spike with latency lower than 0.35 ms. The average threshold charge density was 0.050 +/- 0.005 mC/cm(2), significantly below established safety limits for platinum electrodes. ON and OFF ganglion cells were stimulated with similar efficacy. Repetitive stimulation elicited spikes within a 0.1 ms time window, indicating that the high temporal precision necessary for spike-by-spike stimulation can be achieved in primate retina. Spatial analysis of observed thresholds suggests that electrical activation occurred near the axon hillock, and that dendrites contributed little. Finally, stimulation of a single parasol cell produced little or no activation of other cells in the ON and OFF parasol cell mosaics. The low-threshold, temporally precise, and spatially specific responses hold promise for the application of high-density arrays of small electrodes in epiretinal implants.

Implantation of episcleral electrodes via anterior orbitotomy for stimulation of the retina with induced photoreceptor degeneration: an in vivo feasibility study on a conceptual visual prosthesis

A visual prosthesis is a conceptual device designed to harnesses the function of residual afferent neurons in the visual pathway to produce artificial vision. Such implant, when applied to stimulate the vitreous surface of the retina, has proven feasible in producing the perception of light in both animals and humans. However the practicality of such device has been challenged by the difficulty of surgical access and the risks of damaging the neuroretina. Positioning a visual implant over the scleral surface of the eye could present a safer alternative but this stimulation modality has not been tested in diseased retinas and little is known about the altered electrophysiological properties of the retina in influencing the feasibility of such approach. Experimental photoreceptor degeneration was induced in four pigmented rabbit eyes with systematic administration of a retinotoxic agent, sodium iodate. A multielectrode array was implanted onto the surface of the sclera to target the central and peripheral parts of the retina via an anterior orbitotomy approach. The efficacy of retinal stimulation was assessed by recording electrical evoked potential over the primary visual cortex. The electrical evoked potentials were obtained from both injected and control eyes. The charge density thresholds were found to be similar in both groups and were below the bioelectric safety limit. Spatially differentiated cortical activation profiles were obtained from the central and peripheral retina and the pattern of activation corresponded to the retinotopography of the rabbit primary visual cortex. This study proves that episcleral stimulation of the retina is a feasible alternative to intraocular approaches for the development of a visual prosthesis for retinas with photoreceptor loss.

Retinal Stimulation on Rabbit Using Complementary Metal Oxide Semiconductor Based Multichip Flexible Stimulator toward Retinal Prosthesis

The Functionality of a complementary metal oxide semiconductor (CMOS) LSI-based, multichip flexible retinal stimulator was demonstrated in retinal stimulation experiments on rabbits. A 1×4-configured multichip stimulator was fabricated for application to experiments on animals. An experimental procedure including surgical operations was developed, and retinal stimulation was performed with the fabricated multichip stimulator. Neural responses on the visual cortex were successfully evoked by the fabricated stimulator. The stimulator is confirmed to be applicable to acute animal experiments.

Acyl coenzyme A‐binding protein (ACBP) is phosphorylated and secreted by retinal Müller astrocytes following protein kinase C activation

Horizontal optokinetic stimulation of rabbit retina in vivo evokes increased expression of acyl coenzyme A-binding protein (ACBP), also known as 'diazepam binding inhibitor,' from retinal Müller cells. If the expressed ACBP were also secreted by Müller cells, then stimulus-evoked secretion of ACBP could influence the activity of GABA(A) receptor-expressing retinal neurons. In this study, we examine in vitro whether ACBP is secreted by Müller glial cells and Müller-like QNR/K2 cells following stimulation with elevated levels of KCl and phorbol myristic acetate (PMA). KCl and PMA stimulation evoked secretion of threonine-phosphorylated ACBP. A sequence analysis of ACBP shows that it has five potential phosphorylation sites: Two threonine sites fit a protein kinase C phosphorylation pattern. Two threonine sites fit a casein kinase II (CK2) pattern. One serine site fits a CK2 pattern. As CK2 is not expressed in QNR/K2 cells, it is probable that protein kinase C accounts for the phosphorylation of ACBP in these cells and for the PMA-evoked secretion of ACBP. Serine phosphorylation was constitutive. Horizontal optokinetic stimulation increased threonine-phosphorylated ACBP in rabbit retina. Phosphorylation of ACBP may influence its target affinity. We used a proteolytic fragment of ACBP, octadecaneuropeptide (ODN), to investigate how threonine phosphorylation influences its affinity for GABA(A) receptors. Threonine-phosphorylated ODN had a stronger affinity for GABA(A) receptors than did unphosphorylated ODN or unphosphorylated ACBP. We conclude that stimulus-induced Müller cell secretion of phosphorylated ACBP could influence the GABAergic transmission in neighboring retinal neurons.

A suprachoroidal electrical retinal stimulator design for long-term animal experiments and in vivo assessment of its feasibility and biocompatibility in rabbits.

This article reports on a retinal stimulation system for long-term use in animal electrical stimulation experiments. The presented system consisted of an implantable stimulator which provided continuous electrical stimulation, and an external component which provided preset stimulation patterns and power to the implanted stimulator via a paired radio frequency (RF) coil. A rechargeable internal battery and a parameter memory component were introduced to the implanted retinal stimulator. As a result, the external component was not necessary during the stimulation mode. The inductive coil pair was used to pass the parameter data and to recharge the battery. A switch circuit was used to separate the stimulation mode from the battery recharging mode. The implantable stimulator was implemented with IC chips and the electronics, except for the stimulation electrodes, were hermetically packaged in a biocompatible metal case. A polyimide-based gold electrode array was used. Surgical implantation into rabbits was performed to verify the functionality and safety of this newly designed system. The electrodes were implanted in the suprachoroidal space. Evoked cortical potentials were recorded during electrical stimulation of the retina. Long-term follow-up using OCT showed no chorioretinal abnormality after implantation of the electrodes.

Chronic Intravitreous Infusion of Ciliary Neurotrophic Factor Modulates Electrical Retinal Stimulation Thresholds in the RCS Rat

To determine whether the sustained intravitreous delivery of CNTF modulates cortical response thresholds to electrical retinal stimulation in the RCS rat model of retinal degeneration. Animals were assigned to four groups: untreated, nonsurgical control and infusion groups of 10 ng/d CNTF, 1 ng/d CNTF, and PBS vehicle control. Thresholds for electrically evoked cortical potentials (EECPs) were recorded in response to transcorneal electrical stimulation of the retina at p30 and again at p60, after a three-week infusion. As the retina degenerated over time, EECP thresholds in response to electrical retinal stimulation increased. Eyes treated with 10 ng/d CNTF demonstrated significantly greater retinal sensitivity to electrical stimulation when compared with all other groups. In addition, eyes treated with 1 ng/d CNTF demonstrated significantly greater retinal sensitivity than both PBS-treated and untreated control groups. Retinal sensitivity to electrical stimulation was preserved in animals treated with chronic intravitreous infusion of CNTF. These data suggest that CNTF-mediated retinal neuroprotection may be a novel therapy that can lower stimulus thresholds in patients about to undergo retinal prosthesis implantation. Furthermore, it may maintain the long-term efficacy of these devices in patients.

Retinotopic activation in response to subjective contours in primary visual cortex

Objects in our visual environment are arranged in depth and hence there is a considerable amount of overlap and occlusion in the image they generate on the retina. In order to properly segment the image into figure and background, boundary interpolation is required even across large distances. Here we study the cortical mechanisms involved in collinear contour interpolation using fMRI. Human observers were asked to discriminate the curvature of interpolated boundaries in Kanizsa figures and in control configurations, which contained identical physical information but did not generated subjective shapes. We measured a spatially precise spin-echo BOLD signal and found stronger responses to subjective shapes than non-shapes at the subjective boundary locations, but not at the inducer locations. The responses to subjective contours within primary visual cortex were retinotopically specific and analogous to that to real contours, which is intriguing given that subjective and luminance-defined contours are physically fundamentally different. We suggest that in the absence of retinal stimulation, the observed activation changes in primary visual cortex are driven by intracortical interactions and feedback, which are revealed in the absence of a physical stimulus.

Flexible parylene-based multielectrode array technology for high-density neural stimulation and recording

Novel flexible parylene-based high-density electrode arrays have been developed for functional electrical stimulation in retinal and spinal cord prosthetics. These arrays are microfabricated according to a single-metal-layer process and a revolutionary dual-metal-layer process that promises to meet the needs of extremely high-density stimulation applications. While in many cases thin-film platinum electrodes in parylene C would be sufficient, high surface-area platinum electroplating has been shown to extend the lifetime of stimulated electrodes to more than 430 million pulses without failing. Iridium electrode arrays with higher charge delivery capacity have also been fabricated using a new high-temperature stabilized parylene variant, parylene HT. In addition, a new heat molding process has been implemented to conform electrode arrays to approximate the curvature of canine retinas, and a chronic implantation study of the mechanical effects of parylene-based electrode arrays on the retina over a 6-month follow-up period has provided excellent results. Retinal stimulation from these parylene-based electrode arrays in an isolated tiger salamander preparation was shown to be comparable to light stimulation in terms of generation of action potentials in the inner retina. Finally, electrode arrays have also been implanted and tested on the spinal cords of murine models, with the ultimate goal of facilitation of locomotion after spinal cord injury; these arrays provide a higher density and better spatial control of stimulation and recording than is typically possible using traditional fine-wire electrodes. Spinal cord stimulation typically elicited three muscle responses, an early (direct), a middle (monosynaptic), and a late (polysynaptic) response, classified based on latency after stimulation. Stimulation at different rostrocaudal levels of the cord yielded markedly different muscle responses, highlighting the need for such high-density arrays.

An fMRI study on smooth pursuit and fixation suppression of the optokinetic reflex using similar visual stimulation

This study compares brain activation patterns evoked by smooth pursuit and by fixation suppression of the optokinetic reflex (OKR) using similar retinal stimulation. Functional magnetic resonance imaging (fMRI) was performed during smooth pursuit stimulation in which a moving target was presented on a stationary pattern of stripes, and during fixation suppression of OKR in which a stationary target was presented on a moving pattern of stripes. All subjects could effectively ignore the background pattern and were able to keep the target continuously on the fovea with few saccades, in both experiments. Smooth pursuit evoked activation in the frontal eye fields (FEF), the supplementary eye fields (SEF), the parietal eye fields (PEF), the motion-sensitive area (MT/V5), and in lobules and vermis VI of the cerebellum (oculomotor areas). Fixation suppression of OKR induced activation in the FEF, PEF, and MT/V5. The direct comparison analysis revealed more activation in the right lobule VI of the cerebellum and in the right lingual and calcarine gyri during smooth pursuit than during fixation suppression of OKR. Using similar retinal stimulation, our results show that smooth pursuit and fixation suppression of the OKR appear to activate largely overlapping pathways. The increased activity in the oculomotor areas of the cerebellum during smooth pursuit is probably due to the presence of an active eye movement component.

Synchronized Firing among Retinal Ganglion Cells Signals Motion Reversal

We show that when a moving object suddenly reverses direction, there is a brief, synchronous burst of firing within a population of retinal ganglion cells. This burst can be driven by either the leading or trailing edge of the object. The latency is constant for movement at different speeds, objects of different size, and bright versus dark contrasts. The same ganglion cells that signal a motion reversal also respond to smooth motion. We show that the brain can build a pure reversal detector using only a linear filter that reads out synchrony from a group of ganglion cells. These results indicate that not only can the retina anticipate the location of a smoothly moving object, but that it can also signal violations in its own prediction. We show that the reversal response cannot be explained by models of the classical receptive field and suggest that nonlinear receptive field subunits may be responsible.

Position Selectivity in Scene- and Object-Responsive Occipitotemporal Regions

Complex visual scenes preferentially activate several areas of the human brain, including the parahippocampal place area (PPA), the retrosplenial complex (RSC), and the transverse occipital sulcus (TOS). The sensitivity of neurons in these regions to the retinal position of stimuli is unknown, but could provide insight into their roles in scene perception and navigation. To address this issue, we used functional magnetic resonance imaging (fMRI) to measure neural responses evoked by sequences of scenes and objects confined to either the left or right visual hemifields. We also measured the level of adaptation produced when stimuli were either presented first in one hemifield and then repeated in the opposite hemifield or repeated in the same hemifield. Although overall responses in the PPA, RSC, and TOS tended to be higher for contralateral stimuli than for ipsilateral stimuli, all three regions exhibited position-invariant adaptation, insofar as the magnitude of adaptation did not depend on whether stimuli were repeated in the same or opposite hemifields. In contrast, object-selective regions showed significantly greater adaptation when objects were repeated in the same hemifield. These results suggest that neuronal receptive fields (RFs) in scene-selective regions span the vertical meridian, whereas RFs in object-selective regions do not. The PPA, RSC, and TOS may support scene perception and navigation by maintaining stable representations of large-scale features of the visual environment that are insensitive to the shifts in retinal stimulation that occur frequently during natural vision.

Transcorneal electrical stimulation of retina to treat longstanding retinal artery occlusion

To report the outcome of transcorneal electrical stimulation (TES) of the visual system on long-standing retinal artery occlusion (RAO). Open labeled, case series. Two patients with central RAO (15 and 33 months respectively) and one with branch RAO (26 months) underwent TES therapy. Subjective and objective ophthalmological evaluations were performed before and after the TES. The ages of the patients were 38, 49, and 63 years. The TES (20 Hz biphasic pulses, 30 minutes, up to 1100 uA) was delivered by a bipolar contact lens electrode once a month for 3 months. Perimetric and/or electrophysiological examinations were performed as outcome measures. The visual acuity improved by more than 0.2 logMAR units in two cases, and the visual fields were improved in all three cases. The multifocal ERGs which had been reduced in the loci corresponding to the ischemic retinal area were improved after the treatment in two cases. Neither ocular nor systemic adverse effects were observed except for transient superficial keratitis. TES of the retina can improve retinal function in eyes with long-standing RAOs.

The Effect of Stimulation Frequency and Retinal Stimulus Location on Visual Evoked Potential Topography

The activity of cortical neurons is influenced by retinal stimulus location and temporal modulation. We investigated how reversal frequency of black-and-white checkerboard patterns presented in different parts of the visual field affects evoked potential topography. Visual evoked potentials were recorded from an array of 16 electrodes over the occipital cortex in 12 healthy adults. A checkerboard reversal stimulus (40' check size) was presented with frequencies between 1.95 reversals/s and 7.81 reversals/s in the center or in the left or right hemiretina. Evoked potential fields displayed the well-known components of pattern reversal evoked activity. Computation of FFT and wavelets displayed electrical brain responses directly related to stimulation frequency. Further analysis showed that both retinal stimulus location and stimulation frequency affected visual evoked activity. Field strength as well as scalp field topography changed significantly with different reversal frequency. In addition, the pattern of lateralization of components also depended on temporal frequency of stimulation. Electrical brain activity elicited by visual stimuli shows globally similar features which are modulated by stimulus location and frequency. Our results indicate that--at least partly--different neuronal assemblies are activated by stimuli of different temporal characteristics.

Analysis of quantal size of voltage responses to retinal stimulation in the accessory optic system

In the intact vertebrate central nervous system, the quantal nature of synaptic transmission is difficult to measure because the postsynaptic sites may be distributed along a tortuous dendritic tree that cannot be readily clamped spatially to a uniform potential. Titrating the intact brain's extracellular concentration of calcium ions is also challenging because of its strong buffering mechanisms. In this study, using a whole brain with eye attached preparation, quantal neurotransmission was examined in the turtle brainstem in vitro, by recording from accessory optic system neurons that receive direct input from visually responsive retinal ganglion cells. Unitary EPSPs, evoked by microstimulation of a single ganglion cell, were measured during whole cell current-clamp recordings. In this preparation, the neurons exhibit direction-selectivity, despite the hypoxic conditions. Bath application of cadmium to reduce calcium influx also reduced evoked EPSP amplitudes to that of the spontaneous synaptic events. Statistical analyses indicated that these evoked response amplitudes could be well fitted to a Poisson distribution for most brainstem neurons. Therefore, the spontaneous miniature excitatory synaptic events of approximately 1 mV, as also observed during spike blockade of the retina [Kogo, N., Ariel, M., 1997. Membrane properties and monosynaptic retinal excitation of neurons in the turtle accessory optic system. Journal of Neurophysiology 78, 614–627], are likely responses to the neurotransmitter of single vesicles release by retinal axon terminals.

A new approach towards a minimal invasive retina implant

The possibility of using retina implants (‘retinal prostheses’) for the restoration of basic orientation in blind patients suffering from distal retinal diseases is presently under investigation by at least 18 independent project groups worldwide. It is a common feature of all implants to bypass degenerated retinal layers and to transfer visual information into the retinal network either by direct electrical stimulation or by neurotransmitter release. Contemporary implant designs are differing in the position of stimulating electrodes (epiretinal, subretinal, external) and the anatomical arrangement of implant components (intraocular, extraocular). The latter is of high relevance with regard to possible implant–tissue interactions and biological reactions. During the last few years new types of implants appeared that reduce intraocular components which are now deposited on the outer scleral surface or even in extraorbital position. The extreme of this trend are completely extraocular implants with transchoroidal or extraocular stimulation of the retina. The new type of implant presented in this paper combines the principle of direct retinal stimulation and minimal invasive implantation in a way that stimulating electrodes are the only implant component penetrating the eye via sclera, choroid and retinal pigment epithelium. All other device elements are positioned in extraocular position. The new concept necessitates a paradigmatic change about surgical handling of the choroid and multiple penetrations of the eye. Successful data about this type of retinal prosthesis are already available from long-term observation in non-human primates.

Pigmentation predicts the shift in the line of decussation in humans with albinism

In albinism a large proportion of nerve fibres originating in temporal retina cross the midline at the chiasm and project to the contralateral hemisphere. Studies in rodents with albinism have suggested that the extent of this misrouting at the chiasm is inversely related to pigmentation levels. Here, we examine whether there is evidence for a similar relationship in humans with albinism. Functional MRI was performed on 18 subjects with albinism, 17 control subjects and six controls with nystagmus as they underwent hemifield visual stimulation of nasal or temporal retina. Functional activation in 16 coronal slices beginning at the posterior occipital lobes were analysed and the extent of hemispheric response lateralization at each slice position was determined. During temporal retina stimulation, the control response was lateralized to the hemisphere ipsilateral to the stimulated eye for all slices. In albinos, the response in posterior slices was predominantly in the contralateral hemisphere, consistent with misrouting of temporal retina fibres. However, as slice location became progressively anterior, response lateralization reverted to the ipsilateral hemisphere. The slice location at which the transition from contra- to ipsilateralization occurred provided an estimate of the extent of fibre misrouting in the individual. The slice transition location correlated negatively with pigmentation level, providing the first evidence for a relationship between pigmentation and the extent of misrouting in humans with albinism.

Optical Recording of Retinal and Visual Cortical Responses Evoked by Electrical Stimulation on the Retina

To develop a retinal prosthesis for blind patients using an implanted multielectrode array, it is important to study the response properties of retinal ganglion cells and of the visual cortex to localized retinal electrical stimulation.Optical imaging can reveal the spatio-temporal properties of neuronal activity. Therefore, we conducted a calcium imaging study to investigate response properties to local current stimulation in frog retinas, and a membrane potential imaging study to explore the visual cortical responses to retinal stimulation in guinea pigs.In the retina, local current stimuli evoked transient responses in the ganglion cells located near the stimulus electrode. The spatial pattern of the responding area was altered by changing the location of the stimulation.Local electrical stimulation to the retina also caused transient responses in the visual cortex. The responding cortical areas in the primary visual cortex were localized. A spatially different cortical response was observed to stimulation of a different position on the retina.These results suggest that the imaging study has great potential in revealing the spatio-temporal properties of the neuronal response for the retinal prosthesis.