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Annual Review of Vision Science - Volume 7, 2021
Volume 7, 2021
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Coming of Age in Science: Just Look?
Vol. 7 (2021), pp. 1–17More LessWith Professor Patrick Cavanagh, I started the Harvard Vision Sciences Laboratory in 1990. Blessed with the largesse of a wealthy university, we occupied a very large common space. Here, students pursued their own projects in a uniquely cooperative and exciting scientific environment. The times were just right in the emerging and expanding field of vision science. With good thesis projects under their belt, most of the students went on to successful careers. However, my own coming of age in science did not have such a promising start. It only started well into my thirties when I joined the Smith Kettlewell Eye Research Institute in San Francisco. Providentially, it was there that I had the rare and unique opportunity to work closely and essentially only with peers (not students). Through these intense collaborations, I found my way as a scientist. Most of this account describes these formative years.
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The Diversity of Eyes and Vision
Vol. 7 (2021), pp. 19–41More LessEvery aspect of vision, from the opsin proteins to the eyes and the ways that they serve animal behavior, is incredibly diverse. It is only with an evolutionary perspective that this diversity can be understood and fully appreciated. In this review, I describe and explain the diversity at each level and try to convey an understanding of how the origin of the first opsin some 800 million years ago could initiate the avalanche that produced the astonishing diversity of eyes and vision that we see today. Despite the diversity, many types of photoreceptors, eyes, and visual roles have evolved multiple times independently in different animals, revealing a pattern of eye evolution strictly guided by functional constraints and driven by the evolution of gradually more demanding behaviors. I conclude the review by introducing a novel distinction between active and passive vision that points to uncharted territories in vision research.
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Generating and Using Transcriptomically Based Retinal Cell Atlases
Vol. 7 (2021), pp. 43–72More LessIt has been known for over a century that the basic organization of the retina is conserved across vertebrates. It has been equally clear that retinal cells can be classified into numerous types, but only recently have methods been devised to explore this diversity in unbiased, scalable, and comprehensive ways. Advances in high-throughput single-cell RNA sequencing (scRNA-seq) have played a pivotal role in this effort. In this article, we outline the experimental and computational components of scRNA-seq and review studies that have used them to generate retinal atlases of cell types in several vertebrate species. These atlases have enabled studies of retinal development, responses of retinal cells to injury, expression patterns of genes implicated in retinal disease, and the evolution of cell types. Recently, the inquiry has expanded to include the entire eye and visual centers in the brain. These studies have enhanced our understanding of retinal function and dysfunction and provided tools and insights for exploring neural diversity throughout the brain.
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Morphology, Molecular Characterization, and Connections of Ganglion Cells in Primate Retina
Vol. 7 (2021), pp. 73–103More LessThe eye sends information about the visual world to the brain on over 20 parallel signal pathways, each specialized to signal features such as spectral reflection (color), edges, and motion of objects in the environment. Each pathway is formed by the axons of a separate type of retinal output neuron (retinal ganglion cell). In this review, we summarize what is known about the excitatory retinal inputs, brain targets, and gene expression patterns of ganglion cells in humans and nonhuman primates. We describe how most ganglion cell types receive their input from only one or two of the 11 types of cone bipolar cell and project selectively to only one or two target regions in the brain. We also highlight how genetic methods are providing tools to characterize ganglion cells and establish cross-species homologies.
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Impact of Photoreceptor Loss on Retinal Circuitry
Vol. 7 (2021), pp. 105–128More LessOur sense of sight relies on photoreceptors, which transduce photons into the nervous system's electrochemical interpretation of the visual world. These precious photoreceptors can be disrupted by disease, injury, and aging. Once photoreceptors start to die, but before blindness occurs, the remaining retinal circuitry can withstand, mask, or exacerbate the photoreceptor deficit and potentially be receptive to newfound therapies for vision restoration. To maximize the retina's receptivity to therapy, one must understand the conditions that influence the state of the remaining retina. In this review, we provide an overview of the retina's structure and function in health and disease. We analyze a collection of observations on photoreceptor disruption and generate a predictive model to identify parameters that influence the retina's response. Finally, we speculate on whether the retina, with its remarkable capacity to function over light levels spanning nine orders of magnitude, uses these same adaptational mechanisms to withstand and perhaps mask photoreceptor loss.
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Imaging the Retinal Vasculature
Vol. 7 (2021), pp. 129–153More LessAdvances in retinal imaging are enabling researchers and clinicians to make precise noninvasive measurements of the retinal vasculature in vivo. This includes measurements of capillary blood flow, the regulation of blood flow, and the delivery of oxygen, as well as mapping of perfused blood vessels. These advances promise to revolutionize our understanding of vascular regulation, as well as the management of retinal vascular diseases. This review provides an overview of imaging and optical measurements of the function and structure of the ocular vasculature. We include general characteristics of vascular systems with an emphasis on the eye and its unique status. The functions of vascular systems are discussed, along with physical principles governing flow and its regulation. Vascular measurement techniques based on reflectance and absorption are briefly introduced, emphasizing ways of generating contrast. One of the prime ways to enhance contrast within vessels is to use techniques sensitive to the motion of cells, allowing precise measurements of perfusion and blood velocity. Finally, we provide a brief introduction to retinal vascular diseases.
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The Mechanism of Macular Sparing
Vol. 7 (2021), pp. 155–179More LessPatients with homonymous hemianopia sometimes show preservation of the central visual fields, ranging up to 10°. This phenomenon, known as macular sparing, has sparked perpetual controversy. Two main theories have been offered to explain it. The first theory proposes a dual representation of the macula in each hemisphere. After loss of one occipital lobe, the back-up representation in the remaining occipital lobe is postulated to sustain ipsilateral central vision in the blind hemifield. This theory is supported by studies showing that some midline retinal ganglion cells project to the wrong hemisphere, presumably driving neurons in striate cortex that have ipsilateral receptive fields. However, more recent electrophysiological recordings and neuroimaging studies have cast doubt on this theory by showing only a minuscule ipsilateral field representation in early visual cortical areas. The second theory holds that macular sparing arises because the occipital pole, where the macula is represented, remains perfused after occlusion of the posterior cerebral artery because it receives collateral flow from the middle cerebral artery. An objection to this theory is that it cannot account for reports of macular sparing in patients after loss of an entire occipital lobe. On close scrutiny, such reports turn out to be erroneous, arising from inadequate control of fixation during visual field testing. Patients seem able to detect test stimuli on their blind side within the macula or along the vertical meridian because they make surveillance saccades. A purported treatment for hemianopia, called vision restoration therapy, is based on this error. The dual perfusion theory is supported by anatomical studies showing that the middle cerebral artery perfuses the occipital pole in many individuals.In patients with hemianopia from stroke, neuroimaging shows preservation of the occipital pole when macular sparing is present. The frontier dividing the infarcted territory of the posterior cerebral artery and the preserved territory of the middle cerebral artery is variable, but always falls within the representation of the macula, because the macula is so highly magnified. For physicians, macular sparing was an important neurological sign in acute hemianopia because it signified a posterior cerebral artery occlusion. Modern neuroimaging has supplanted the importance of that clinical sign but at the same time confirmed its validity. For patients, macular sparing remains important because it mitigates the impact of hemianopia and preserves the ability to read fluently.
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Neuromodulatory Control of Early Visual Processing in Macaque
Vol. 7 (2021), pp. 181–199More LessVisual processing is dynamically controlled by multiple neuromodulatory molecules that modify the responsiveness of neurons and the strength of the connections between them. In particular, modulatory control of processing in the lateral geniculate nucleus of the thalamus, V1, and V2 will alter the outcome of all subsequent processing of visual information, including the extent to and manner in which individual inputs contribute to perception and decision making and are stored in memory. This review addresses five small-molecule neuromodulators—acetylcholine, dopamine, serotonin, noradrenaline, and histamine—considering the structural basis for their action, and the effects of their release, in the early visual pathway of the macaque monkey. Traditionally, neuromodulators are studied in isolation and in discrete circuits; this review makes a case for considering the joint action of modulatory molecules and differences in modulatory effects across brain areas as a better means of understanding the diverse roles that these molecules serve.
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Visual Signals in the Mammalian Auditory System
Vol. 7 (2021), pp. 201–223More LessCoordination between different sensory systems is a necessary element of sensory processing. Where and how signals from different sense organs converge onto common neural circuitry have become topics of increasing interest in recent years. In this article, we focus specifically on visual–auditory interactions in areas of the mammalian brain that are commonly considered to be auditory in function. The auditory cortex and inferior colliculus are two key points of entry where visual signals reach the auditory pathway, and both contain visual- and/or eye movement–related signals in humans and other animals. The visual signals observed in these auditory structures reflect a mixture of visual modulation of auditory-evoked activity and visually driven responses that are selective for stimulus location or features. These key response attributes also appear in the classic visual pathway but may play a different role in the auditory pathway: to modify auditory rather than visual perception. Finally, while this review focuses on two particular areas of the auditory pathway where this question has been studied, robust descending as well as ascending connections within this pathway suggest that undiscovered visual signals may be present at other stages as well.
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Population Models, Not Analyses, of Human Neuroscience Measurements
Vol. 7 (2021), pp. 225–255More LessSelectivity for many basic properties of visual stimuli, such as orientation, is thought to be organized at the scale of cortical columns, making it difficult or impossible to measure directly with noninvasive human neuroscience measurement. However, computational analyses of neuroimaging data have shown that selectivity for orientation can be recovered by considering the pattern of response across a region of cortex. This suggests that computational analyses can reveal representation encoded at a finer spatial scale than is implied by the spatial resolution limits of measurement techniques. This potentially opens up the possibility to study a much wider range of neural phenomena that are otherwise inaccessible through noninvasive measurement. However, as we review in this article, a large body of evidence suggests an alternative hypothesis to this superresolution account: that orientation information is available at the spatial scale of cortical maps and thus easily measurable at the spatial resolution of standard techniques. In fact, a population model shows that this orientation information need not even come from single-unit selectivity for orientation tuning, but instead can result from population selectivity for spatial frequency. Thus, a categorical error of interpretation can result whereby orientation selectivity can be confused with spatial frequency selectivity. This is similarly problematic for the interpretation of results from numerous studies of more complex representations and cognitive functions that have built upon the computational techniques used to reveal stimulus orientation. We suggest in this review that these interpretational ambiguities can be avoided by treating computational analyses as models of the neural processes that give rise to measurement. Building upon the modeling tradition in vision science using considerations of whether population models meet a set of core criteria is important for creating the foundation for a cumulative and replicable approach to making valid inferences from human neuroscience measurements.
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Visual Remapping
Vol. 7 (2021), pp. 257–277More LessOur visual system is fundamentally retinotopic. When viewing a stable scene, each eye movement shifts object features and locations on the retina. Thus, sensory representations must be updated, or remapped, across saccades to align presaccadic and postsaccadic inputs. The earliest remapping studies focused on anticipatory, presaccadic shifts of neuronal spatial receptive fields. Over time, it has become clear that there are multiple forms of remapping and that different forms of remapping may be mediated by different neural mechanisms. This review attempts to organize the various forms of remapping into a functional taxonomy based on experimental data and ongoing debates about forward versus convergent remapping, presaccadic versus postsaccadic remapping, and spatial versus attentional remapping. We integrate findings from primate neurophysiological, human neuroimaging and behavioral, and computational modeling studies. We conclude by discussing persistent open questions related to remapping, with specific attention to binding of spatial and featural information during remapping and speculations about remapping's functional significance.
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Role of the Superior Colliculus in Guiding Movements Not Made by the Eyes
Vol. 7 (2021), pp. 279–300More LessThe superior colliculus (SC) has long been associated with the neural control of eye movements. Over seventy years ago, the orderly topography of saccade vectors and corresponding visual field locations were discovered in the cat SC. Since then, numerous high-impact studies have investigated and manipulated the relationship between visuotopic space and saccade vector across this topography to better understand the physiological underpinnings of the sensorimotor signal transformation. However, less attention has been paid to the other motor responses that may be associated with SC activity, ranging in complexity from concerted movements of skeletomotor muscle groups, such as arm-reaching movements, to behaviors that involve whole-body movement sequences, such as fight-or-flight responses in murine models. This review surveys these more complex movements associated with SC (optic tectum in nonmammalian species) activity and, where possible, provides phylogenetic and ethological perspective.
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Spatial Integration in Normal Face Processing and Its Breakdown in Congenital Prosopagnosia
Vol. 7 (2021), pp. 301–321More LessCongenital prosopagnosia (CP), a life-long impairment in face processing that occurs in the absence of any apparent brain damage, provides a unique model in which to explore the psychological and neural bases of normal face processing. The goal of this review is to offer a theoretical and conceptual framework that may account for the underlying cognitive and neural deficits in CP. This framework may also provide a novel perspective in which to reconcile some conflicting results that permits the expansion of the research in this field in new directions. The crux of this framework lies in linking the known behavioral and neural underpinnings of face processing and their impairments in CP to a model incorporating grid cell–like activity in the entorhinal cortex. Moreover, it stresses the involvement of active, spatial scanning of the environment with eye movements and implicates their critical role in face encoding and recognition. To begin with, we describe the main behavioral and neural characteristics of CP, and then lay down the building blocks of our proposed model, referring to the existing literature supporting this new framework. We then propose testable predictions and conclude with open questions for future research stemming from this model.
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Urgent Decision Making: Resolving Visuomotor Interactions at High Temporal Resolution
Vol. 7 (2021), pp. 323–348More LessMeasuring when exactly perceptual decisions are made is crucial for defining how the activation of specific neurons contributes to behavior. However, in traditional, nonurgent visuomotor tasks, the uncertainty of this temporal measurement is very large. This is a problem not only for delimiting the capacity of perception, but also for correctly interpreting the functional roles ascribed to choice-related neuronal responses. In this article, we review psychophysical, neurophysiological, and modeling work based on urgent visuomotor tasks in which this temporal uncertainty can be effectively overcome. The cornerstone of this work is a novel behavioral metric that describes the evolution of the subject's perceptual judgment moment by moment, allowing us to resolve numerous perceptual events that unfold within a few tens of milliseconds. In this framework, the neural distinction between perceptual evaluation and motor selection processes becomes particularly clear, as the conclusion of one is not contingent on that of the other.
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Remembering the Past to See the Future
Vol. 7 (2021), pp. 349–365More LessIn addition to the role that our visual system plays in determining what we are seeing right now, visual computations contribute in important ways to predicting what we will see next. While the role of memory in creating future predictions is often overlooked, efficient predictive computation requires the use of information about the past to estimate future events. In this article, we introduce a framework for understanding the relationship between memory and visual prediction and review the two classes of mechanisms that the visual system relies on to create future predictions. We also discuss the principles that define the mapping from predictive computations to predictive mechanisms and how downstream brain areas interpret the predictive signals computed by the visual system.
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Balancing Flexibility and Interference in Working Memory
Vol. 7 (2021), pp. 367–388More LessWorking memory is central to cognition, flexibly holding the variety of thoughts needed for complex behavior. Yet, despite its importance, working memory has a severely limited capacity, holding only three to four items at once. In this article, I review experimental and computational evidence that the flexibility and limited capacity of working memory reflect the same underlying neural mechanism. I argue that working memory relies on interactions between high-dimensional, integrative representations in the prefrontal cortex and structured representations in the sensory cortex. Together, these interactions allow working memory to flexibly maintain arbitrary representations. However, the distributed nature of working memory comes at the cost of causing interference between items in memory, resulting in a limited capacity. Finally, I discuss several mechanisms used by the brain to reduce interference and maximize the effective capacity of working memory.
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Binocular Vision and Stereopsis Across the Animal Kingdom
Vol. 7 (2021), pp. 389–415More LessMost animals have at least some binocular overlap, i.e., a region of space that is viewed by both eyes. This reduces the overall visual field and raises the problem of combining two views of the world, seen from different vantage points, into a coherent whole. However, binocular vision also offers many potential advantages, including increased ability to see around obstacles and increased contrast sensitivity. One particularly interesting use for binocular vision is comparing information from both eyes to derive information about depth. There are many different ways in which this might be done, but in this review, I refer to them all under the general heading of stereopsis. This review examines the different possible uses of binocular vision and stereopsis and compares what is currently known about the neural basis of stereopsis in different taxa. Studying different animals helps us break free of preconceptions stemming from the way that stereopsis operates in human vision and provides new insights into the different possible forms of stereopsis.
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Lightness Perception in Complex Scenes
Vol. 7 (2021), pp. 417–436More LessLightness perception is the perception of achromatic surface colors: black, white, and shades of grey. Lightness has long been a central research topic in experimental psychology, as perceiving surface color is an important visual task but also a difficult one due to the deep ambiguity of retinal images. In this article, I review psychophysical work on lightness perception in complex scenes over the past 20 years, with an emphasis on work that supports the development of computational models. I discuss Bayesian models, equivalent illumination models, multidimensional scaling, anchoring theory, spatial filtering models, natural scene statistics, and related work in computer vision. I review open topics in lightness perception that seem ready for progress, including the relationship between lightness and brightness, and developing more sophisticated computational models of lightness in complex scenes.
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Quantifying Visual Image Quality: A Bayesian View
Vol. 7 (2021), pp. 437–464More LessImage quality assessment (IQA) models aim to establish a quantitative relationship between visual images and their quality as perceived by human observers. IQA modeling plays a special bridging role between vision science and engineering practice, both as a test-bed for vision theories and computational biovision models and as a powerful tool that could potentially have a profound impact on a broad range of image processing, computer vision, and computer graphics applications for design, optimization, and evaluation purposes. The growth of IQA research has accelerated over the past two decades. In this review, we present an overview of IQA methods from a Bayesian perspective, with the goals of unifying a wide spectrum of IQA approaches under a common framework and providing useful references to fundamental concepts accessible to vision scientists and image processing practitioners. We discuss the implications of the successes and limitations of modern IQA methods for biological vision and the prospect for vision science to inform the design of future artificial vision systems. (The detailed model taxonomy can be found at http://ivc.uwaterloo.ca/research/bayesianIQA/.)
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The Certainty of Ambiguity in Visual Neural Representations
Vol. 7 (2021), pp. 465–486More LessSome images evoke bistable percepts: two different visual experiences seen in alternation while continuously viewing an unchanged stimulus. The Necker Cube and Rubin's Vase are classic examples, each of which gives alternating percepts of different shapes. Other bistable percepts are alternating colors or directions of motion. Although stimuli that result in salient bistability are rare and sometimes cleverly constructed to emphasize ambiguity, they have been influential for over 150 years, since the work of von Helmholtz, who considered them to be evidence for perceptual visual processes that interpret retinal stimuli. While bistability in natural viewing is uncommon, the main point of this review is that implicit ambiguity in visual neural representations is pervasive. Resolving ambiguity, therefore, is a fundamental and ubiquitous process of vision that routinely affects what we see, not an oddity arising from cleverly crafted images. This review focuses on the causes of widespread ambiguity, historical perspectives on it, and modern knowledge and theory about resolving it.
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Reading: The Confluence of Vision and Language
Vol. 7 (2021), pp. 487–517More LessThe scientific study of reading has a rich history that spans disciplines from vision science to linguistics, psychology, cognitive neuroscience, neurology, and education. The study of reading can elucidate important general mechanisms in spatial vision, attentional control, object recognition, and perceptual learning, as well as the principles of plasticity and cortical topography. However, literacy also prompts the development of specific neural circuits to process a unique and artificial stimulus. In this review, we describe the sequence of operations that transforms visual features into language, how the key neural circuits are sculpted by experience during development, and what goes awry in children for whom learning to read is a struggle.
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Eyewitness Identification Is a Visual Search Task
Vol. 7 (2021), pp. 519–541More LessThe simultaneous six-pack photo lineup is a standard eyewitness identification procedure, consisting of one police suspect plus five physically similar fillers. The photo lineup is either a target-present array (the suspect is guilty) or a target-absent array (the suspect is innocent). The eyewitness is asked to search the six photos in the array with respect to a target template stored in memory (namely, the memory of the perpetrator's face). If the witness determines that the perpetrator is in fact in the lineup (detection), then the next step is to specify the position of the perpetrator's face in the lineup (localization). The witness may also determine that the perpetrator is not present and reject the lineup. In other words, a police lineup is a detection-plus-localization visual search task. Signal detection concepts that have long guided thinking about visual search have recently had a significant impact on our understanding of police lineups.
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Face Recognition by Humans and Machines: Three Fundamental Advances from Deep Learning
Vol. 7 (2021), pp. 543–570More LessDeep learning models currently achieve human levels of performance on real-world face recognition tasks. We review scientific progress in understanding human face processing using computational approaches based on deep learning. This review is organized around three fundamental advances. First, deep networks trained for face identification generate a representation that retains structured information about the face (e.g., identity, demographics, appearance, social traits, expression) and the input image (e.g., viewpoint, illumination). This forces us to rethink the universe of possible solutions to the problem of inverse optics in vision. Second, deep learning models indicate that high-level visual representations of faces cannot be understood in terms of interpretable features. This has implications for understanding neural tuning and population coding in the high-level visual cortex. Third, learning in deep networks is a multistep process that forces theoretical consideration of diverse categories of learning that can overlap, accumulate over time, and interact. Diverse learning types are needed to model the development of human face processing skills, cross-race effects, and familiarity with individual faces.
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Mobile Computational Photography: A Tour
Vol. 7 (2021), pp. 571–604More LessThe first mobile camera phone was sold only 20 years ago, when taking pictures with one's phone was an oddity, and sharing pictures online was unheard of. Today, the smartphone is more camera than phone. How did this happen? This transformation was enabled by advances in computational photography—the science and engineering of making great images from small-form-factor, mobile cameras. Modern algorithmic and computing advances, including machine learning, have changed the rules of photography, bringing to it new modes of capture, postprocessing, storage, and sharing. In this review, we give a brief history of mobile computational photography and describe some of the key technological components, including burst photography, noise reduction, and super-resolution. At each step, we can draw naive parallels to the human visual system.
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Lexical Color Categories
Vol. 7 (2021), pp. 605–631More LessColor is a continuous variable, and humans can distinguish more than a million colors, yet world color lexicons contain no more than a dozen basic color terms. It has been understood for 160 years that the number of color terms in a lexicon varies greatly across languages, yet the lexical color categories defined by these terms are similar worldwide. Starting with the seminal study by Berlin and Kay, this review considers how and why this is so. Evidence from psychological, linguistic, and computational studies has advanced our understanding of how color categories came into being, how they contribute to our shared understanding of color, and how the resultant categories influence color perception and cognition. A key insight from the last 50 years of research is how human perception and the need for communication within a society worked together to create color lexicons that are somewhat diverse, yet show striking regularities worldwide.
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Aging of the Retina: Molecular and Metabolic Turbulences and Potential Interventions
Vol. 7 (2021), pp. 633–664More LessMultifaceted and divergent manifestations across tissues and cell types have curtailed advances in deciphering the cellular events that accompany advanced age and contribute to morbidities and mortalities. Increase in human lifespan during the past century has heightened awareness of the need to prevent age-associated frailty of neuronal and sensory systems to allow a healthy and productive life. In this review, we discuss molecular and physiological attributes of aging of the retina, with a goal of understanding age-related impairment of visual function. We highlight the epigenome–metabolism nexus and proteostasis as key contributors to retinal aging and discuss lifestyle changes as potential modulators of retinal function. Finally, we deliberate promising intervention strategies for promoting healthy aging of the retina for improved vision.
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Retina Metabolism and Metabolism in the Pigmented Epithelium: A Busy Intersection
Vol. 7 (2021), pp. 665–692More LessThe outer retina is nourished from the choroid, a capillary bed just inside the sclera. O2, glucose, and other nutrients diffuse out of the choroid and then filter through a monolayer of retinal pigment epithelium (RPE) cells to fuel the retina. Recent studies of energy metabolism have revealed striking differences between retinas and RPE cells in the ways that they extract energy from fuels. The purpose of this review is to suggest and evaluate the hypothesis that the retina and RPE have complementary metabolic roles that make them depend on each other for survival and for their abilities to perform essential and specialized functions.
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Optical Coherence Tomography and Glaucoma
Vol. 7 (2021), pp. 693–726More LessEarly detection and monitoring are critical to the diagnosis and management of glaucoma, a progressive optic neuropathy that causes irreversible blindness. Optical coherence tomography (OCT) has become a commonly utilized imaging modality that aids in the detection and monitoring of structural glaucomatous damage. Since its inception in 1991, OCT has progressed through multiple iterations, from time-domain OCT, to spectral-domain OCT, to swept-source OCT, all of which have progressively improved the resolution and speed of scans. Even newer technological advancements and OCT applications, such as adaptive optics, visible-light OCT, and OCT-angiography, have enriched the use of OCT in the evaluation of glaucoma. This article reviews current commercial and state-of-the-art OCT technologies and analytic techniques in the context of their utility for glaucoma diagnosis and management, as well as promising future directions.
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Genetic Determinants of Intraocular Pressure
Vol. 7 (2021), pp. 727–746More LessIntraocular pressure (IOP) is the cardinal and only modifiable risk factor for glaucoma, the leading cause of irreparable blindness worldwide. Twin and family studies estimate the heritability of IOP to be 40–70%, and linkage studies for IOP have identified numerous loci. Mutations in MYOC can cause markedly elevated IOP and aggressive glaucoma often requiring surgical intervention. However, the majority of the genetic basis for raised IOP and glaucoma in populations is complex, and recent large genome-wide association studies (GWASs) have identified over 100 common variants that contribute to IOP variation. In combination, these loci are predictive for primary open-angle glaucoma in independent populations, achieving an area under the receiver operating characteristic curve of 76% for high-pressure primary open-angle glaucoma; this suggests the possibility of targeted screening in the future. Additionally, GWAS findings have identified important biological pathways underlying IOP regulation, including lymphangiogenesis and lipid metabolism, providing novel targets for new therapies.
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Measures of Function and Structure to Determine Phenotypic Features, Natural History, and Treatment Outcomes in Inherited Retinal Diseases
Vol. 7 (2021), pp. 747–772More LessInherited retinal diseases (IRDs) are at the forefront of innovative gene-specific treatments because of the causation by single genes, the availability of microsurgical access for treatment delivery, and the relative ease of quantitative imaging and vision measurement. However, it is not always easy to choose a priori, from scores of potential measures, an appropriate subset to evaluate efficacy outcomes considering the wide range of disease stages with different phenotypic features. This article reviews measurements of visual function and retinal structure that our group has used over the past three decades to understand the natural history of IRDs. We include measures of light sensitivity, retinal structure, mapping of natural fluorophores, evaluation of pupillary light reflex, and oculomotor control. We provide historical context and examples of applicability. We also review treatment trial outcomes using these measures of function and structure.
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Eye Movements in Macular Degeneration
Vol. 7 (2021), pp. 773–791More LessIn healthy vision, the fovea provides high acuity and serves as the locus for fixation achieved through saccadic eye movements. Bilateral loss of the foveal regions in both eyes causes individuals to adopt an eccentric locus for fixation. This review deals with the eye movement consequences of the loss of the foveal oculomotor reference and the ability of individuals to use an eccentric fixation locus as the new oculomotor reference. Eye movements are an integral part of everyday activities, such as reading, searching for an item of interest, eye–hand coordination, navigation, or tracking an approaching car. We consider how these tasks are impacted by the need to use an eccentric locus for fixation and as a reference for eye movements, specifically saccadic and smooth pursuit eye movements.
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Functional Organization of Extraocular Motoneurons and Eye Muscles
Vol. 7 (2021), pp. 793–825More LessEye movements are indispensable for visual image stabilization during self-generated and passive head and body motion and for visual orientation. Eye muscles and neuronal control elements are evolutionarily conserved, with novel behavioral repertoires emerging during the evolution of frontal eyes and foveae. The precise execution of eye movements with different dynamics is ensured by morphologically diverse yet complementary sets of extraocular muscle fibers and associated motoneurons. Singly and multiply innervated muscle fibers are controlled by motoneuronal subpopulations with largely selective premotor inputs from task-specific ocular motor control centers. The morphological duality of the neuromuscular interface is matched by complementary biochemical and molecular features that collectively assign different physiological properties to the motor entities. In contrast, the functionality represents a continuum where most motor elements contribute to any type of eye movement, although within preferential dynamic ranges, suggesting that signal transmission and muscle contractions occur within bands of frequency-selective pathways.
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Axonal Growth Abnormalities Underlying Ocular Cranial Nerve Disorders
Vol. 7 (2021), pp. 827–850More LessAbnormalities in cranial motor nerve development cause paralytic strabismus syndromes, collectively referred to as congenital cranial dysinnervation disorders, in which patients cannot fully move their eyes. These disorders can arise through one of two mechanisms: (a) defective motor neuron specification, usually by loss of a transcription factor necessary for brainstem patterning, or (b) axon growth and guidance abnormalities of the oculomotor, trochlear, and abducens nerves. This review focuses on our current understanding of axon guidance mechanisms in the cranial motor nerves and how disease-causing mutations disrupt axon targeting. Abnormalities of axon growth and guidance are often limited to a single nerve or subdivision, even when the causative gene is ubiquitously expressed. Additionally, when one nerve is absent, its normal target muscles attract other motor neurons. Study of these disorders highlights the complexities of axon guidance and how each population of neurons uses a unique but overlapping set of axon guidance pathways.
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Precision Medicine Trials in Retinal Degenerations
Vol. 7 (2021), pp. 851–865More LessThe beginning of the twenty-first century was marked by the innovative use of pharmacochemical interventions, which have since expanded to include gene-based molecular therapies. For years, treatment has focused on tackling the pathophysiology of monogenic orphan diseases, and one of the first applications of these novel genome editing technologies was the treatment of rare inherited retinal dystrophies. In this review, we present recent, ongoing, and future gene therapy–based treatment trials for choroideremia, X-linked retinitis pigmentosa, Stargardt disease, and age-related macular degeneration. As these trials pave the way toward halting the progression of such devastating diseases, we will begin to see the exciting development of newer, cutting-edge strategies including base editing and prime editing, ushering in a new era of precision medicine.
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Best Practices for the Design of Clinical Trials Related to the Visual System
Vol. 7 (2021), pp. 867–886More LessClinical trials for conditions affecting the visual system need to not only conform to the guidelines for all clinical trials, but also accommodate the possibility of both eyes of a single patient qualifying for the trial. In this review, I present the interplay of the key components in the design of a clinical trial, along with the modifications or options that may be available for trials addressing ocular conditions. Examples drawn from published reports of the design and results of clinical trials of ocular conditions are provided to illustrate application of the design principles. Current approaches to data analysis and reporting of trials are outlined, and the oversight and regulatory procedures to protect participants in clinical trials are discussed.
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