Strabismus, Amblyopia, and Visual Processing Program
The Strabismus, Amblyopia, and Visual Processing Program supports clinical and laboratory research on visual development, neural processing, eye movement, and other disorders involving output of the retina and other portions of the brain that serve vision. Knowledge of the normal visual system provides a foundation for understanding the causes of impaired vision and developing corrective measures.
Over the past several decades, visual neuroscience funded by the NEI has exerted a substantial influence on other fields of neuroscience. This is especially true of developmental and functional studies of the central visual pathways, which continue to yield results that can be generalized to the brain as a whole. During the past 5 years, improvements in noninvasive brain imaging techniques, visual testing, and probability-based models of visual perception and new discoveries in axonal guidance and related developmental events have enhanced the understanding of visual function and factors that influence the development, maintenance, and regeneration of the visual system.
Future vision research that employs promising new technologies and collaborations with new disciplines, such as bioengineering, holds great promise for understanding the development and function of the visual and oculomotor systems. Progress in the diagnosis and treatment of clinical disorders that impair vision, such as amblyopia, strabismus, myopia, and oculomotor disorders, depends on cutting-edge research. The future promise and close link between clinical practice and research are reflected in the overarching Program goals below.
After evaluating the Program, the Strabismus, Amblyopia, and Visual Processing Panel recommends the following goals for the next 5-year period:
- Determine the etiology of myopia in humans, identify the risk factors associated with myopia and other refractive errors, and identify the biochemical pathways associated with the control of eye growth.
- Understand how the visual system develops, its capacity for plasticity, and ways to promote its regeneration.
- Investigate the development of visual function in children at high risk for amblyopia and strabismus, determine underlying mechanisms, and develop and disseminate information about detection methods and therapeutic interventions for restoring normal vision.
- Analyze visual performance in normal and dysfunctional states and develop clinically useful diagnostic tests for assessing visual performance, particularly in infants and young children.
- Understand the neural circuitry and muscular mechanisms that control gaze under environmental conditions and discover the mechanisms that provide plasticity to the oculomotor system.
- Understand how the brain processes visual information, how neural activity is related to visual perception, and how visual processing interacts with other brain systems underlying cognition.
Advances over the past 5 years have had an important influence on understanding the development of the visual system and brain. The visual system has long been an ideal model system for understanding how development sculpts brain organization and for studying CNS regeneration. It is ideal because of its accessibility and high degree of organization in a variety of animal models.
A key advance has been in identifying and describing the molecules in developing visual pathways that guide retinal axonal outgrowth to appropriate targets in the developing nervous system.
An important series of advances have been made in understanding the molecular control of synaptic specificity and topographical mapping. Genetic model systems have begun to reveal the genes necessary for synapse formation and the molecular mechanism by which topographical mapping in the brain is achieved.
There has also been progress in understanding regenerative failure in the CNS. Glial cell molecules that inhibit regeneration of axons have been identified, and there is evidence that they can be neutralized to enhance regeneration.
Another step forward has been a clearer understanding of the mechanisms providing plasticity to the developing visual system, with discoveries of the roles of activity and sleep and of the molecular and cellular mechanisms underlying critical periods of development. Appropriate neurotrophic peptide receptors and electrical activity have been shown to affect cell survival, rate of dendritic and axonal growth, and the establishment of neural connections. The molecular mechanism by which activity regulates specificity and synaptogenesis in the visual system has been the subject of intensive study over the past several years, illuminating a number of molecular mechanisms.
Progress also has been made over the past 5 years in understanding amblyopia and strabismus. Evidence has emerged showing that patching and penalization treatment regimens can successfully manage amblyopia in children. Recent studies of large populations with amblyopia show distinctive and systematic variations in the patterns of functional loss in amblyopia and the effect of binocularity in these conditions. A better understanding of risk factors and neural mechanisms related to amblyopia and strabismus, plus earlier screening of children, has improved treatment and clinical outcomes.
Progress continues to be made in myopia research, including a refinement in the understanding of visual and biochemical cues and genes involved in the regulation of eye growth and refractive states. Experimental studies have shown, for example, that quality, quantity, and timing of visual stimuli can affect ocular growth, which could influence the development of new treatments. Discovery of the role of circadian rhythms and of the molecular changes in the sclera driven by signals from the retina has increased understanding of eye growth. Clinical studies are examining whether certain optical or pharmacological treatments can slow the progression of myopia in children, while epidemiological studies are identifying risk factors, both environmental and genetic, and are determining the incidence of myopia in the United States and elsewhere.
Also significant is progress in understanding the influence of the oculomotor tissues on eye movements, motor neurons, extraocular muscles, and connective tissues within the orbit. The orbit contains mechanical relationships that support functions previously thought to require complex neural inputs. The emergence of the concept of pulley arrangements will affect diagnostic, clinical, and surgical approaches to the treatment of oculomotor disorders.
Researchers have acquired new details about the neural mechanisms that control the initiation, direction, and duration of eye movements, including the brainstem mechanisms responsible for saccadic eye movement and the cortical mechanisms responsible for control of gaze. Progress is being made in understanding the relationship between eye movements and the posture or movement of the limbs and head.
New techniques for obtaining intracellular recordings from the intact brain of mammals are increasing the understanding of the circuitry of the visual system. Descriptions of the connectivity between visual areas of the cortex and subcortical afferents continue to be refined and are leading to better descriptions of hierarchical relationships in the brain. Evidence is emerging suggesting that the pattern of visual inputs may play a role in refining developing neural circuits. Parallels between and limits to the presumed homology of the human visual system and that of nonhuman primates also are emerging. It is important to recognize that research on nonhuman primates will continue to play an essential role in understanding the human visual system in health and disease.
A number of studies have shown that contextual cues markedly alter the percept of a given retinal image feature. This has led to the recognition that context plays a fundamental role in the formation of perceptual or scene-based representations in the visual system. This transformation is accomplished at relatively early stages in visual processing. A view of perceptual constancy has emerged in which different retinal stimuli with common environmental causes elicit the same percept. These studies have revealed neuronal responses that vary over time, reflecting the pattern perceived rather than the retinal stimulus.
Studies of visual processing have identified neuronal activity that is correlated with the decision to execute a particular action in response to a particular visual stimulus, rather than simply correlated with either the stimulus or the action alone. These studies have led to promising theories and have identified neuronal substrates in which visual information is mapped to action.
A better understanding of the cell types and their connections in the visual cortical areas has given rise to the idea that there may be fundamental circuits that underlie visual function. This information enhances computational and theoretical approaches to understanding how these circuits function.
Among the advances of the past 5 years has been the refinement of noninvasive neuroimaging technologies. Research using this approach has provided new insights about how the human visual cortex is organized. It has confirmed understanding of the human visual system previously established by anatomical and physiological studies in animals. It has advanced knowledge of the brain processes involved in visual motor function and attention and is providing new insights into neural deficits in abnormalities such as amblyopia and brain reorganization following injury and in oculomotor function. The development and application of imaging technologies at the cellular level have provided important insights into developmental processes, such as axonal guidance, and have led to the discovery of dendritic spine motility underlying both plasticity and development.
After considering the research advances that have been made in this Program and on the basis of an analysis of research needs and opportunities, the Strabismus, Amblyopia, and Visual Processing Panel recommends the following laboratory and clinical research objectives:
- Determine how stem cells differentiate in the development of the visual system and how they can be used to understand the molecular logic of cell-type-specific identity in the visual system. Develop a clearer understanding of the molecular and cellular signals influencing the growth of axons and the axonal cytoskeleton. Understand how and why axons stop growing once they reach their targets and the mechanisms that control development and maintenance of synapses. Gain an understanding of the mechanisms that control arealization and specification in the visual cortex.
- Elucidate the mechanism of the critical period to determine how experience alters connectivity in the developing visual system. Develop an understanding of how environment and vision influence neural activity in developing circuits and how these interactions alter gene expression and the molecular changes that alter circuit properties.
- Further study the mechanisms that lead to degeneration and regeneration of the central visual pathways, including ganglion cell death and optic nerve regeneration. Determine the basis for CNS regenerative failure. Develop a clearer understanding of the molecular and cellular interactions within the CNS in the context of both normal function and neurodegenerative disorders of the eye and the central visual pathways.
- Develop and apply new recording approaches, electrical or optical, to determine how synaptic input and output give rise to properties such as receptive fields at any level in the visual pathways. Study the function, circuitry, and development of higher order visual areas to determine the effect of attention and top-down influences on visual processing.
- Expand the knowledge of myopia by further characterizing the visual signals that govern eye growth. Identify the genes and gene products associated with these signaling mechanisms. Identify the human risk factors, environmental and genetic, for myopia and abnormal eye growth. Evaluate the efficacy of potential treatments, such as pharmacological approaches, special spectacles, and contact lenses, for slowing the progression of myopia.
- Develop and use innovative approaches to detect and treat strabismus and amblyopia. Develop imaging technologies to further understand the neural basis of amblyopia and related visual deficits. Identify the underlying genetic components related to strabismus and oculomotor disorders. Translate knowledge into tests for reliable screening and early diagnosis.
- Within each processing stage in the visual system, determine the relationships among neuronal cell morphology, laminar position, input patterns, output targets, and encoded sensory information. Understand how the patterns of circuitry within and among visual areas account for the influence of stimulus context on neuronal responsivity. Identify the role that inhibitory circuits play in higher visual processing.
- Determine the cellular mechanisms that give rise to changes in visual sensitivity associated with attention and perceptual learning. Discover the larger role of neuronal plasticity in the formation of visual associative memories and imagery. Develop a mechanistic understanding of the origin of the signals that control attention and how they alter the responses of neurons in visual processing and sensorimotor transformations.
- Bridge the knowledge of what happens at the cellular level in the visual system with the knowledge of visual psychophysics. Develop molecular/cellular approaches and imaging technologies to gain an understanding of the role of the cell activity that underlies behavior. Exploit the knowledge of the functional organization of the visual system in animal models with noninvasive imaging studies in humans.
- Attain a clearer understanding of how signals are processed within cortical circuits for voluntary eye movements and characterize the signals that pass from cortical motor circuits to subcortical and cerebellar circuits. Develop a better understanding of the cellular mechanisms underlying plasticity in the oculomotor system that ensure accurate gaze shift and alignment of the eyes.
- Develop a better understanding of the neural control, biomechanical properties, and anatomical relationships of the tissues around the eye muscles and the roles they play in guiding eye movements.
- Encourage the development and application of emerging technologies that will affect the progress of vision research in the future. Examples include genetic engineering, proteomics, imaging technologies at the cellular and systems levels, development of reagents that signal neural function, and bioinformatics. Encourage collaboration among vision researchers, clinicians, computational scientists, and bioengineers to fully exploit these emerging technologies.