Comparative effectiveness between two types of head-mounted magnification modes using a smartphone-based virtual display.

SIGNIFICANCE: This work shows the benefits of using two different magnification strategies to improve the reading ability of low-vision patients using a head-mounted technology. PURPOSE: The aim of this study was to conduct a comparative clinical trial evaluating the effectiveness of two magnification strategies in a head-mounted virtual reality display. METHODS: Eighty-eight eligible low-vision subjects were randomized into two arms: (1) the full-field magnification display or (2) the virtual bioptic telescope mode. Subjects completed baseline testing and received training on how to use the device properly and then took the device home for a 2- to 4-week intervention period. An adaptive rating scale questionnaire (Activity Inventory) was administered before and after the intervention (home trial) period to measure the effect of the system. A Simulator Sickness Questionnaire was also administered. Baseline and follow-up results were analyzed using Rasch analysis to assess overall effectiveness of each magnification mode for various functional domain categories. RESULTS: Both magnification modes showed a positive effect for reading, visual information, and the overall goals functional domain categories, with only reading reaching statistical significance after correction for multiple comparisons. However, there were no significant between-group differences between the two modes. The results of the Simulator Sickness Questionnaire showed that the magnification modes of the head-mounted display device were overall well tolerated among low-vision users. CONCLUSIONS: Both the full-field and virtual bioptic magnification strategies were effective in significantly improving functional vision outcomes for self-reported reading ability.

Preliminary Evaluation of Two Digital Image Processing Strategies for Head-Mounted Magnification for Low Vision Patients.

PURPOSE: In an observational clinical outcome study, we tested the effectiveness and use of the combination of two innovative approaches to magnification: a virtual bioptic telescope and a virtual projection screen, implemented with digital image processing in a head-mounted display (HMD) equipped with a high-resolution video camera and head trackers. METHODS: We recruited 30 participants with best-corrected visual acuity <20/100 in the better-seeing eye and bilateral central scotomas. Participants were trained on the HMD system, then completed a 7- to 10-day in-home trial. The Activity Inventory was administered before and after the home trial to measure the effect of system use on self-reported visual function. A simulator sickness questionnaire (SSQ) and a system-use survey were administered. Rasch analysis was used to assess outcomes. RESULTS: Significant improvements were seen in functional ability measures estimated from goal difficulty ratings (Cohen's d = 0.79, P < 0.001), and reading (d = 1.28, P < 0.001) and visual information (d = 1.11, P < 0.001) tasks. There was no improvement in patient-reported visual motor function or mobility. One participant had moderately severe discomfort symptoms after SSQ item calibration. The average patient rating of the system's use was 7.14/10. CONCLUSIONS: Use of the system resulted in functional vision improvements in reading and visual information processing. Lack of improvement in mobility and visual motor function is most likely due to limited field of view, poor depth perception, and lack of binocular disparity. TRANSLATIONAL RELEVANCE: We determine if these new image processing approaches to magnification are beneficial to low vision patients performing everyday activities.

Low Vision Enhancement with Head-mounted Video Display Systems: Are We There Yet?

SIGNIFICANCE: Head-mounted video display systems and image processing as a means of enhancing low vision are ideas that have been around for more than 20 years. Recent developments in virtual and augmented reality technology and software have opened up new research opportunities that will lead to benefits for low vision patients. Since the Visionics low vision enhancement system (LVES), the first head-mounted video display LVES, was engineered 20 years ago, various other devices have come and gone with a recent resurgence of the technology over the past few years. In this article, we discuss the history of the development of LVESs, describe the current state of available technology by outlining existing systems, and explore future innovation and research in this area. Although LVESs have now been around for more than two decades, there is still much that remains to be explored. With the growing popularity and availability of virtual reality and augmented reality technologies, we can now integrate these methods within low vision rehabilitation to conduct more research on customized contrast-enhancement strategies, image motion compensation, image-remapping strategies, and binocular disparity, all while incorporating eye-tracking capabilities. Future research should use this available technology and knowledge to learn more about the visual system in the low vision patient and extract this new information to create prescribable vision enhancement solutions for the visually impaired individual.

Amacrine-to-amacrine cell inhibition: Spatiotemporal properties of GABA and glycine pathways.

We measured the spatial and temporal properties of GABAergic and glycinergic inhibition to amacrine cells in the whole-mount rabbit retina. The amacrine cells were parsed into two morphological classes: narrow-field cells with processes spreading less than 200 µm and wide-field cells with processes extending more than 300 µm. The inhibition was also parsed into two types: sustained glycine and transient GABA. Narrow-field amacrine cells receive 1) very transient GABAergic inhibition with a fast onset latency of 140 ± 16 ms decaying to 30% of the peak level within 208 ± 27 ms elicited broadly over a lateral distance of up to 1500 µm and 2) sustained glycinergic inhibition with a medium onset latency of 286 ± 23 ms that was elicited over a spatial area often broader than the processes of the narrow-field amacrine cells. Wide-field amacrine cells received sustained glycinergic inhibition but no broad transient GABAergic inhibition. Surprisingly, neither of these amacrine cell classes received sustained local GABAergic inhibition, commonly found in an earlier study of ganglion cells.

The retinal hypercircuit: a repeating synaptic interactive motif underlying visual function.

The vertebrate retina generates a stack of about a dozen different movies that represent the visual world as dynamic neural images or movies. The stack is embodied as separate strata that span the inner plexiform layer (IPL). At each stratum, ganglion cell dendrites reach up to read out inhibitory interactions between three different amacrine cell classes that shape bipolar-to-ganglion cell transmission. The nexus of these five cell classes represents a functional module, a retinal 'hypercircuit', that is repeated across the surface of each of the dozen strata that span the depth of the IPL. Individual differences in the characteristics of each cell class at each stratum lead to the unique processing characteristics of each neural image throughout the stack. This review shows how the interactions between the morphological and physiological characteristics of each cell class generate many of the known retinal visual functions including motion detection, directional selectivity, local edge detection, looming detection, object motion and looming detection.

Differential targeting of optical neuromodulators to ganglion cell soma and dendrites allows dynamic control of center-surround antagonism.

Retinal degenerative diseases cause photoreceptor loss and often result in remodeling and deafferentation of the inner retina. Fortunately, ganglion cell morphology appears to remain intact long after photoreceptors and distal retinal circuitry have degenerated. We have introduced the optical neuromodulators channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR) differentially into the soma and dendrites of ganglion cells to recreate antagonistic center-surround receptive field interactions. We then reestablished the physiological receptive field dimensions of primate parafoveal ganglion cells by convolving Gaussian-blurred versions of the visual scene at the appropriate wavelength for each neuromodulator with the Gaussians inherent in the soma and dendrites. These Gaussian-modified ganglion cells responded with physiologically relevant antagonistic receptive field components and encoded edges with parafoveal resolution. This approach bypasses the degenerated areas of the distal retina and could provide a first step in restoring sight to individuals suffering from retinal disease.

Retinal synaptic pathways underlying the response of the rabbit local edge detector.

We studied the circuitry that underlies the behavior of the local edge detector (LED) retinal ganglion cell in rabbit by measuring the spatial and temporal properties of excitatory and inhibitory currents under whole cell voltage clamp. Previous work showed that LED excitation is suppressed by activity in the surround. However, the contributions of outer and inner retina to this characteristic and the neurotransmitters used are currently unknown. Blockage of retinal inhibitory pathways (GABA(A), GABA(C), and glycine) eliminated edge selectivity. Inverting gratings in the surround with 50-microm stripe sizes did not stimulate horizontal cells, but suppressed on and off excitation by roughly 60%, indicating inhibition of bipolar terminals (feedback inhibition). On pharmacologic blockage, we showed that feedback inhibition used both GABA(A) and GABA(C) receptors, but not glycine. Glycinergic inhibition suppressed GABAergic feedback inhibition in the center, enabling larger excitatory currents in response to luminance changes. Excitation, feedback inhibition, and direct (feedforward) inhibition responded to luminance-neutral flipping gratings of 20- to 50-microm widths, showing they are driven by independent subunits within their receptive fields, which confers sensitivity to borders between areas of texture and nontexture. Feedforward inhibition was glycinergic, its rise time was faster than decay time, and did not function to delay spiking at the onset of a stimulus. Both the on and off phases could be triggered by luminance shifts as short in duration as 33 ms and could be triggered during scenes that already produced a high baseline level of feedforward inhibition. Our results show how LED circuitry can use subreceptive field sensitivity to detect visual edges via the interaction between excitation and feedback inhibition and also respond to rapid luminance shifts within a rapidly changing scene by producing feedforward inhibition.

Six different roles for crossover inhibition in the retina: correcting the nonlinearities of synaptic transmission.

Early retinal studies categorized ganglion cell behavior as either linear or nonlinear and rectifying as represented by the familiar X- and Y-type ganglion cells in cat. Nonlinear behavior is in large part a consequence of the rectifying nonlinearities inherent in synaptic transmission. These nonlinear signals underlie many special functions in retinal processing, including motion detection, motion in motion, and local edge detection. But linear behavior is also required for some visual processing tasks. For these tasks, the inherently nonlinear signals are "linearized" by "crossover inhibition." Linearization utilizes a circuitry whereby nonlinear ON inhibition adds with nonlinear OFF excitation or ON excitation adds with OFF inhibition to generate a more linear postsynaptic voltage response. Crossover inhibition has now been measured in most bipolar, amacrine, and ganglion cells. Functionally crossover inhibition enhances edge detection, allows ganglion cells to recognize luminance-neutral patterns with their receptive fields, permits ganglion cells to distinguish contrast from luminance, and maintains a more constant conductance during the light response. In some cases, crossover extends the operating range of cone-driven OFF ganglion cells into the scotopic levels. Crossover inhibition is also found in neurons of the lateral geniculate nucleus and V1.

Three forms of spatial temporal feedforward inhibition are common to different ganglion cell types in rabbit retina.

There exist more than 30 different morphological amacrine cell types, but there may be fewer physiological types. Here we studied the amacrine cell outputs by measuring the temporal and spatial properties of feedforward inhibition to four different types of ganglion cells. These ganglion cells, each with concentric receptive field organization, appear to receive a different relative contribution of the same three forms of feed-forward inhibition, namely: local glycinergic, local sustained GABAergic, and broad transient GABAergic inhibition. Two of these inhibitory components, local glycinergic inhibition and local sustained GABAergic inhibition were localized to narrow regions confined to the dendritic fields of the ganglion cells. The third, a broad transient GABAergic inhibition, was driven from regions peripheral to the dendritic area. Each inhibitory component is also correlated with characteristic kinetics expressed in all ganglion cells: broad transient GABAergic inhibition had the shortest latency, local glycinergic inhibition had an intermediate latency, and local sustained GABAergic inhibition had the longest latency. We suggest each of these three inhibitory components represents the output from a distinct class of amacrine cell, mediates a specific visual function, and each forms a basic functional component for the four ganglion cell types. Similar subunits likely exist in the circuits of other ganglion cell types as well.

Crossover inhibition in the retina: circuitry that compensates for nonlinear rectifying synaptic transmission.

In the mammalian retina, complementary ON and OFF visual streams are formed at the bipolar cell dendrites, then carried to amacrine and ganglion cells via nonlinear excitatory synapses from bipolar cells. Bipolar, amacrine and ganglion cells also receive a nonlinear inhibitory input from amacrine cells. The most common form of such inhibition crosses over from the opposite visual stream: Amacrine cells carry ON inhibition to the OFF cells and carry OFF inhibition to the ON cells ("crossover inhibition"). Although these synapses are predominantly nonlinear, linear signal processing is required for computing many properties of the visual world such as average intensity across a receptive field. Linear signaling is also necessary for maintaining the distinction between brightness and contrast. It has long been known that a subset of retinal outputs provide exactly this sort of linear representation of the world; we show here that rectifying (nonlinear) synaptic currents, when combined thorough crossover inhibition can generate this linear signaling. Using simple mathematical models we show that for a large set of cases, repeated rounds of synaptic rectification without crossover inhibition can destroy information carried by those synapses. A similar circuit motif is employed in the electronics industry to compensate for transistor nonlinearities in analog circuits.

Amacrine-to-amacrine cell inhibition in the rabbit retina.

We studied the interactions between excitation and inhibition in morphologically identified amacrine cells in the light-adapted rabbit retinal slice under patch clamp. The majority of on amacrine cells received glycinergic off inhibition. About half of the off amacrine cells received glycinergic on inhibition. Neither class received any GABAergic inhibition. A minority of on, off, and on-off amacrine cells received both glycinergic on and GABAergic off inhibition. These interactions were found in cells with diverse morphologies having both wide and narrow processes that stratify in single or multiple layers of the inner plexiform layer (IPL). Most on-off amacrine cells received no inhibition and have monostratified processes confined to the middle of the IPL. The most common interaction between amacrine cells that we measured was "crossover inhibition," where off inhibits on and on inhibits off. Although the morphology of amacrine cells is diverse, the interactions between excitation and inhibition appear to be relatively limited and specific.

Symmetric interactions within a homogeneous starburst cell network can lead to robust asymmetries in dendrites of starburst amacrine cells.

Starburst amacrine cells in the mammalian retina respond asymmetrically to movement along their dendrites; centrifugal movement elicits stronger responses in each dendrite than centripetal movement. It has been suggested that the asymmetrical response can be attributed to intrinsic properties of the processes themselves. But starburst cells are known to release and have receptors for both GABA and acetylcholine. We tested whether interactions within the starburst cell network can contribute to their directional response properties. In a computational model of interacting starburst amacrine cells, we simulated the response of individual dendrites to moving light stimuli. By setting the model parameters for "synaptic connection strength" (cs) to positive or negative values, overlapping starburst dendrites could either excite or inhibit each other. For some values of cs, we observed a very robust inward/outward asymmetry of the starburst dendrites consistent with the reported physiological findings. This is the case, for example, if a starburst cell receives inhibition from other starburst cells located in its surround. For other values of cs, individual dendrites can respond best either to inward movement or respond symmetrically. A properly wired network of starburst cells can therefore account for the experimentally observed asymmetry of their response to movement, independent of any internal biophysical or biochemical properties of starburst cell dendrites.

Parallel processing in retinal ganglion cells: how integration of space-time patterns of excitation and inhibition form the spiking output.

Our goal was to understand how patterns of excitation and inhibition, interacting across arrays of ganglion cells in space and time, generate the spiking output pattern for each ganglion cell type. We presented the retina with a 1-s flashed square, 600 microm on a side, and measured patterns of excitation and inhibition over an 1,800-microm-wide region encompassing many ganglion cells. Excitatory patterns of on ganglion cells resembled rectified versions of the voltage patterns of on bipolar cells. Inhibitory patterns in on ganglion cells resembled the rectified versions of voltage patterns of off bipolar cells. off ganglion cells received off excitation and on inhibition. Many ganglion cells also received an additional wide field transient inhibition derived from the activity of both on and off bipolar cells. Ganglion cell spiking was suppressed in those space-time regions dominated by inhibition. We classified each ganglion cell type by correlating its space-time patterns with its dendritic morphology. These studies suggest the bipolar and amacrine cell circuitry underlying the interplay between on and off signals that generate spiking patterns in ganglion cells. They reveal a surprising synergistic interaction between excitation and inhibition in most ganglion cells.

Directional selectivity is formed at multiple levels by laterally offset inhibition in the rabbit retina.

The excitatory and inhibitory inputs to directionally selective (DS) ganglion cells are themselves directionally selective. Directionality is achieved because excitation is reduced during null-direction movement along a GABAergic pathway. Inhibition is reduced during preferred-direction movement along a pathway that includes cholinergic synapses. Both excitation and inhibition are made directional by laterally offset inhibitory signals similar to the spatial offset of the direct inhibitory input to the DS cell dendrites. Thus, spatially offset lateral inhibition generates directionality at three different levels in the DS circuitry. We also found that for stimuli falling within the dendritic field, cholinergic input is delivered to the OFF but not the ON dendrites. Cholinergic pathways from outside the dendritic field reach both ON and OFF dendrites, but both of these pathways are normally inactivated by GABAergic synapses.

Mechanisms and circuitry underlying directional selectivity in the retina.

In the retina, directionally selective ganglion cells respond with robust spiking to movement in their preferred direction, but show minimal response to movement in the opposite, or null, direction. The mechanisms and circuitry underlying this computation have remained controversial. Here we show, by isolating the excitatory and inhibitory inputs to directionally selective cells and measuring direct connections between these cells and presynaptic neurons, that a presynaptic interneuron, the starburst amacrine cell, delivers direct inhibition to directionally selective cells. The processes of starburst cells are connected asymmetrically to directionally selective cells: those pointing in the null direction deliver inhibition; those pointing in the preferred direction do not. Starburst cells project inhibition laterally ahead of a stimulus moving in the null direction. In addition, starburst inhibition is itself directionally selective: it is stronger for movement in the null direction. Excitation in response to null direction movement is reduced by an inhibitory signal acting at a site that is presynaptic to the directionally selective cell. The interplay of these components generates reduced excitation and enhanced inhibition in the null direction, thereby ensuring robust directional selectivity.