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Report of the Strabismus, Amblyopia, and Visual Processing Panel

PROGRAM OVERVIEW AND GOALS

How do we see? This simple question does not have a simple answer. Vision is a complex series of events that begins when light enters our eyes and ends with perception. We can discriminate between objects of different size, contrast, and color, and we can track moving objects with precision. We routinely perform these tasks over an enormous range of light intensity. Our vision system easily outperforms any manmade machine.

Disruption of any part of the visual system severely impairs our ability to see. Disturbances in neural and ocular development, metabolism, neural processing, and eye movements lead to serious visual impairment such as amblyopia (a developmental abnormality of the central nervous system [CNS] that causes impaired vision in one or both eyes), strabismus (misalignment of the eyes), nystagmus (continuously moving eyes), scotoma (local areas of blindness), myopia (near-sightedness), and other conditions that require strong spectacle lenses. Over 30 million people in the United States suffer from one or more of these visual disorders. These disorders cause substantial visual loss that interferes with learning, working, and overall quality of life.

The Strabismus, Amblyopia, and Visual Processing (SAVP) Program of the National Eye Institute (NEI) supports both clinical and laboratory research on development, neural processing, eye movement, and associated disorders involving the output of retina and those portions of the brain that serve vision. Studies on normal and impaired vision go hand-in-hand. Detailed knowledge of the normal visual system provides the foundation for understanding the causes of impaired vision and for developing corrective measures.

Photo of a lab technique.

Research sponsored by the SAVP Program involves a variety of model species, but the primary goal is to understand the human visual system and alleviate its disorders. Many powerful laboratory techniques have contributed new knowledge about the visual system, but these methods are not suitable in humans. Therefore, a variety of animal species are used to simulate human states. Primates are the model system closest to the human, but species ranging from invertebrates, such as flies and horseshoe crabs, to nonprimate mammals, such as cats and rabbits, have yielded and will continue to yield significant information on the fundamental mechanisms of vision common to all species, including humans. Past vision research demonstrated the wisdom of this approach: key insights generally come from model systems that are well suited for exploring a specific research question. Past research also demonstrates the wisdom of using primates for investigations directly related to the human visual system.

Over the last three decades, visual neuroscience has had a substantial impact on other fields of neuroscience. This is especially true for developmental and functional studies of the central visual pathways, which have yielded results that have been generalized to the brain as a whole. In developmental neuroscience, the increasing power and sophistication of molecular approaches has led, over the past 5 years, to an explosion of new information on the basic molecular mechanisms that guide the initial formation and connectivity of the nervous system in general and the visual system in particular. The accessibility of visual pathways, such as the optic nerve, has enabled scientists to develop powerful models for studying regeneration in the adult CNS. Moreover, decades of investment in the study of the structure, function, and development of the visual system-supported in large part by the SAVP Program of the NEI-have made this the system of choice to study the effects of genetic and molecular manipulations like gene deletions (knockouts) or gene insertions (knockins and transgenics). Spurred by new optical and electrical recording techniques, similarly impressive advances have improved understanding of synaptic and activity-based patterns that guide plastic rearrangements in the developing visual system and the basis of critical periods. These phenomena have provided a conceptual spur to research in childhood developmental disorders and on learning and memory throughout the brain.

In systems neuroscience, the SAVP Program has traditionally supported cutting-edge research into the brain systems underlying visual perception and underlying movements of the eyes. New knowledge resulting from this investment has now brought systems neuroscience to the threshold of a new era in which physiologists can ask incisive questions about how sophisticated visual information, encoded at the highest levels of the cortical visual system, can guide motor planning decisions implemented at the highest levels of the oculomotor system. At this watershed between traditionally defined sensory and motor systems reside many of the higher brain functions that are critical to cognition—attention, memory, volitional decision-making, and the representation and awareness of space. This rapidly developing field encompassing neuroscientific study of these brain functions is known as "cognitive neuroscience," and vision research will continue to play a leading role in this arena of inquiry. Thus, exciting new dividends are being realized from the substantial investment in basic systems-level research made by this Program over the past several decades.

In Fiscal Year 1997, the NEI funded 340 extramural research projects in the Strabismus, Amblyopia, and Visual Processing Program at a total cost of $61,316,048.

Future vision research coupled with emerging technology hold great promise for understanding the development and normal function of visual and oculomotor systems. Progress in the diagnosis and treatment of clinical disorders that impair vision, such as amblyopia, myopia, nystagmus, and strabismus, critically depends on laboratory research. Both the future promise and the close link between clinical practice and research are reflected in the overarching goals of the SAVP Program:

ASSESSMENT OF PROGRESS

Research in the SAVP Program has been unusually productive during the past 5 years. Important advances have been made in the clinical analysis and treatment of specific diseases, as well as in basic understanding of the development and normal function of the visual and oculomotor systems. Following are a few of the salient advances, particularly those that follow directly from the goals and objectives of the NEI's last 5-year plan.

Demonstration that the growth of the eye and the development of accurate focus (refractive state) are guided by visual feedback during early life.Myopia, or nearsightedness, is a common condition in which images of distant objects are focused in front of, instead of on, the retina, usually because the eye is too long. Myopia occurs in approximately 25 percent of the population of the United States. After extensive argument about whether to attribute myopia to visual factors or genetic factors, experimentation on animals in the past two decades has provided a clearer, but as yet incomplete, picture of some of the processes involved in the control of refractive error in growing eyes. Two insights are especially important. First, images not focused on the retina guide the developing eye to correct for this defocus. Thus, animals with either hyperopia (farsightedness) or myopia imposed by spectacle lenses alter the shape of their eyes to bring the images back into focus. Second, changes in focus of images on the retina can cause changes in eye growth directly by a cascade of chemical signals from the retina to the sclera. Thus, in animals, normal refractive development and myopia of moderate severity may involve a visual feedback mechanism that controls eye growth. Recent evidence that this feedback occurs in primates suggests that these discoveries have substantial practical implications for the clinical treatment of myopia and other refractive disorders in humans, affording opportunities for testing this hypothesis in clinical trials.

Early detection and intervention in strabismus and amblyopia.Concerted efforts in many laboratories over the past two decades have led to the realization that many strabismic and amblyopic states result from abnormal visual experience in early life that can be prevented or reversed with early detection and intervention. Many barriers still need to be overcome in the national fight against these disorders, including proper education of healthcare professionals and the general population, access to quality health care across socioeconomic classes, and the steady cooperation of families during long-term treatment of infants. In terms of scientific understanding and clinical capability, however, researchers have now arrived at a point where most amblyopias can be successfully treated given early detection and appropriate intervention.

Molecular, genetic, and neural insights into disease states affecting the extraocular muscles and the eyelid. Each eye is served by six extraocular muscles that enable the vast range of eye movements humans make to explore the world and stabilize visual objects on the retina. In addition, each eye is served by an eyelid and blink reflex, which protect the eye from potential injury and ensure that the cornea is regularly moistened. Dysfunction in the extraocular muscles, the muscles that control the eyelid, or the nerves that serve any of these muscles can result in serious impairment of vision in the affected eye. Researchers have made significant progress in understanding several of these disease states in the last 5 years. For example, the extraocular muscles seem to be immune from the effects of Duchenne muscular dystrophy, even though skeletal muscles degenerate throughout the remainder of the body. Thus, extraocular muscles are structurally and functionally different from those of other motor systems. This unique phenotype raises the possibility that extraocular muscles will respond in a unique manner to many disease states. Recent evidence also suggests that specific genes regulate the development of specific motoneuron pools, and that mutations in these genes could be etiologic factors in congenital disorders that affect ocular motility. A host of clinical disorders affects movements of the eyelid. Fortunately, adaptive "reprogramming" of the neural drive to the muscles of the eyelid can compensate for the effects of these disorders and restore eyeblinks to a near-normal state. New studies have shown, however, that this natural reprogramming can go awry, producing blepharospasm, which results in uncontrollable and prolonged spasms of eyelid closure. Relying on laboratory research concerning the neural mechanism of reprogramming and the details of the neural circuitry controlling the eyelids, researchers have now developed animal models of blepharospasm. These models provide a springboard for testing new treatments for a disorder that afflicts 10 percent of the population over the age of 70.

Discovery of specific gene mutations that cause Leber's Hereditary Optic Neuropathy.Leber's Hereditary Optic Neuropathy (LHON) is a maternally inherited genetic disease that results in substantial loss of central vision in affected patients. Most genetic diseases are caused by mutations in chromosomal DNA inside the cell nucleus. LHON, however, is the first disease to be associated with mutations of the small amounts of DNA that reside inside the mitochondria (mtDNA). This DNA encodes for subunits of complex 1 of the respiratory chain, the key biochemical cascade that manufactures the cell's supply of the high-energy molecule adenosine triphosphate. The three most common mutations causing LHON have now been identified, providing a useful diagnostic test for LHON and new insight into the pathogenesis of the disease.

Completion of the Ischemic Optic Neuropathy Decompression Trial. Ischemic optic neuropathy is the most common pathology of the optic nerve, other than glaucoma, affecting older persons. The Ischemic Optic Neuropathy Decompression Trial was a randomized clinical trial designed to compare patients who received a commonly used surgical procedure with those who were carefully observed but had no surgery. This trial has been completed except for long-term followup studies. Results from this study indicate that decompression surgery, a difficult and expensive procedure, is no better than careful followup (in terms of improved vision) and possibly worse. This finding will result in substantial savings in medical costs and will put fewer people at risk to an unnecessary surgical procedure.

Discovery of molecular and cellular mechanisms that regulate cell growth, survival, and death. In contrast to peripheral nerves, the CNS (including the retina and the optic nerve) is extremely limited in its capacity for regrowth after injury. The primary hope for correcting this situation lies in understanding the underlying mechanisms that mediate cell growth, survival, and death. This field has witnessed explosive growth in the past 5 years, with one exciting discovery following another. For example, experiments in Drosophila, zebrafish, and mice have identified master control genes for eye formation. In humans, mutations of one of these genes account for a genetic disorder called aniridia, which causes retinal, lens, and iris defects. Additional developmental studies have uncovered a specific class of molecules (called POU domain transcription factors) that govern the expression of specific genes during development, thereby playing an essential role in establishing different classes of retinal ganglion cells. Proper myelination of the growing nerve appears to be ensured by a different traffic of chemical signals between growing retinal ganglion cells and oligodendrocytes, the cells that ultimately form the myelin sheath around the developing axon. Oligodendrocytes that fail to contact an unmyelinated axon undergo programmed cell death (apoptosis). Many of the genes that underlie this apoptotic "cell suicide" program have been identified and are expressed by most animal cells, including retinal ganglion cells. Survival of retinal neurons is promoted by a class of peptide trophic signals, including the recently discovered bcl-2, which inhibits activation of the cell suicide program. Overexpression of bcl-2 can rescue injured retinal ganglion cells from almost certain death. Finally, it has become possible in recent years to isolate developing retinal ganglion cells and grow them in tissue culture. This preparation has revealed that survival of retinal ganglion cells requires not only peptide factors such as the neurotrophins, but also intrinsic electrical activity. All of these exciting discoveries have critically important implications for the regeneration of damaged visual pathways, and therefore comprise a high priority area for future research.

Discovery of molecular mechanisms mediating topographic order and axon guidance within the developing visual system. Representation of the visual world in the form of topographic maps is a basic organizational principle of the visual system in all vertebrate animals, including humans. Topographic maps exist in numerous structures throughout the brain and are crucial to the ability to perceive an organized visual world and move in a goal-directed manner within this world. Among the most dramatic advances of the last 5 years has been the discovery of specific molecular factors that mediate the formation of topographic order within the developing visual system. For example, complementary gradients of a specific class of cell surface ligands and their receptors—members of the Eph family of tyrosine kinases—are distributed in a graded manner across topographic maps in the retinotectal system. These gradients are crucial to establishing topographic maps in these structures. Other related molecules are also distributed throughout the visual system and appear to play a fundamental role in guiding growing nerve processes to their targets. Another discovery of fundamental importance in this field is identification of molecules called netrins and semaphorins, which are chemoattractant (or chemorepulsive) molecules that guide growing axons and form the refined pattern of connections throughout the vertebrate nervous system. Research on how these cell surface and diffusible molecules function will be crucial for understanding the inhibitors of regeneration of the optic nerve, the barriers to establishing new nerve connections, and the design of rational therapies to enhance these processes.

Imaging the functional architecture of the visual cortex.One of the major accomplishments over the past 5 years in the area of functional processing has been the advent of new strategies for minimally invasive optical imaging of the brain. Using what has now become a straightforward technology, it is now possible to visualize the functional organization of exposed visual areas with an unprecedented degree of spatial resolution. This has led to the first complete descriptions of the organization of orientation and ocular dominance domains in striate cortex and the relationship between the two. Increasingly sophisticated stimulus paradigms have allowed investigators to visualize sites of motion and color processing in the striate and extrastriate cortices of carnivores and primates. Optical imaging of intrinsic cortical signals was developed in the visual system, but it was the anatomical and physiological data from decades of vision research that allowed the validity of this approach to be assessed rigorously. Intrinsic signal imaging is now being employed in less well-studied cortical areas, and studies in the visual system have paved the way for clinical investigations to identify epileptic foci in humans. This provides yet another example of how laboratory research on visual processing has enabled an entirely new technology to move into clinical applications. The ability to rapidly visualize the functional architecture of the cortex has allowed the consequences of visual deprivation in strabismus and amblyopic conditions to be assessed directly and provide a further guide for detailed electrophysiological investigations.

Identification and mapping of higher cortical visual areas that serve vision and eye movement control in humans.The human visual cortex is composed of a primary visual area (V1), whose integrity is necessary for functional vision of any sort, and higher order areas that play important roles in more specific aspects of vision, such as object recognition or spatial orientation. These higher visual areas and the pathways that connect them have been investigated in great detail in monkeys and cats, but little progress has been made in analyzing higher regions of the human visual system, because researchers have not been able to carry out appropriate experiments in humans. The advent of noninvasive imaging technologies like positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have now changed this situation dramatically. For the first time, researchers are able to peer inside the living human brain and assess visual function with reasonable spatial and temporal resolution.

Several research groups have now identified and topographically mapped visual areas V2, V3, V3A, and portions of V4 in humans. In addition, several research groups have studied a region called the middle temporal area (MT or V5), which may be specifically involved in the analysis of visual motion information. The spatial layout and topographic organization of these areas are remarkably similar to the general primate plan deduced over the past 30 years from painstaking studies in several species of monkeys. More recently, similar information has begun to emerge for the control of eye movements by the cerebral cortex, which will certainly be an active area of research in the future. This turn of events is encouraging, not only because of the new knowledge gained concerning the human visual system, but also because it confirms the wisdom of the substantial investment in research on animal models made by the SAVP Program over the past three decades.

The ongoing discovery of central neural mechanisms governing perceptual sensitivity to visual stimuli.The visual system has a limited capacity for processing the vast amounts of visual information that flood the two eyes throughout each day. Exquisitely sensitive mechanisms at several levels of the visual pathway work together to distribute this limited processing capacity to match the organism's most pressing needs. Some of these mechanisms are said to be "bottom-up," in that they are an intrinsic feature of local neural circuits in the visual cortex and operate automatically on all visual information arriving at the cortex. Substantial progress has been made in the past 5 years in understanding the process of contrast gain control, which adjusts the response properties of cortical neurons according to the range of contrasts present in the visual scene during a given epoch of time. Evidence indicates that this scaling of neural sensitivity is achieved by response "normalization," in which the output of each cortical neuron is effectively divided by the pooled activity of a large number of additional neurons that analyze the same small region of visual space. Other mechanisms governing the sensitivity of cortical neurons are said to be "top-down," in the sense that they reflect voluntary decisions made by the organism to pay attention to certain objects, features, or locations in the visual environment.

Visual attention can be manipulated in alert animals using simple behavioral paradigms borrowed from cognitive psychology, and these behavioral manipulations exert dramatic effects on the responses of neurons in higher order regions of the visual cortex. In essence, attention acts as a powerful filter, suppressing unimportant information and passing behaviorally relevant information on to higher processing stages. Over the past 5 years, powerful attentional effects have been demonstrated at surprisingly early levels of the cortical pathway, and neural correlates have been demonstrated both for spatial attention (the "spotlight" hypothesis) and for feature-based attention. Another major influence on visual sensitivity is perceptual learning. The past 5 years have yielded a flood of behavioral studies demonstrating that practice on specific perceptual tasks results in increased sensitivity to weak visual signals and increased capacity for discriminating among very similar signals, which can be sharply restricted to the region of space in which the important signal commonly occurs. Thus, the adult visual system is not immutable, can change according to behavioral demands, and has implications for potential rehabilitation after injury.

Novel insights into mechanisms for transforming visual information into signals appropriate for guiding motor behavior.Humans use visual information to judge location, size, and shape of objects to predict the future position of those objects. This information is captured by nerve cells in the retina and is therefore represented in a coordinate frame that changes with every movement of the eyes (eye-centered coordinates). To catch, grasp, approach, or avoid such objects, however, information must be transformed from eye-centered coordinates to a body-centered coordinate system appropriate for moving the arms, legs, or hands. Vision researchers have made important strides in the last 5 years in understanding how the brain performs this feat. Psychophysical studies of human observers have shown that visual and nonvisual signals are used to make the coordinate transformations needed to perceive object position with respect to the body. The nonvisual signals are provided by the motor commands sent to the eye and neck muscles and by the commands sent by the vestibular system. Physiological studies suggest that there are a number of intermediate representations of space between visual input and motor output.

Recent work on perceived self-motion through the environment has led to further insight. Psychophysical and modeling studies have demonstrated that this optic flow pattern can be used to compute the observer's future position with respect to obstacles and landmarks. Psychophysical research has shown that humans are exceedingly adept at interpreting these complex flow patterns, a capability that requires information about the motor signals sent to the eyes and head in addition to the visual flow signals falling on the retina. Physiological studies have identified neural circuits in a cortical area called MST that receives a combination of visual flow, eye movement, and head position signals appropriate for solving the self-motion problem. These circuits and the role they play in computing self-motion will certainly be a topic of active experimentation in the future.

Combined, these accomplishments illustrate the wide scope and vitality of research in the SAVP Program—from molecular factors underlying the early development of the nervous system, to the neural processes mediating human visual perception, and finally to insights leading to the correction or prevention of visual impairments.

PROGRAM OBJECTIVES

The needs and opportunities related to each of these objectives and the strategies for accomplishing them will now be considered.

Objective 1(a): Identify the visual error signals that govern eye growth during correction for refractive error.

Research Needs and Opportunities

In animal models, it is now accepted that visual circumstances can influence refractive error, and that this influence involves modification of the growth of the eye. Thus, a feedback mechanism is at work in ocular growth—visual input influences growth, which in turn modifies the visual input. Importantly, the influence of vision on growth can be communicated directly from the retina to the sclera without involvement of the brain. This view of the mechanisms of refractive adjustments has provoked a search for the visual cues the retina uses to discern whether to accelerate or retard the axial growth of the eye and for the signals, presumably chemical, by which the retina communicates to the sclera the appropriate direction of growth. The most provocative candidates are dopamine and acetylcholine because agonists and antagonists, respectively, reduce form-deprivation myopia in both birds and primates.

Strategic Research Questions

What visual signals are used by the retina to regulate growth? What are the chemical signals that permit the retina to communicate with the sclera? How do humoral signals move from the retina through the barrier of the retinal pigment epithelium? If there is a cascade of chemical signals involving several cell types, what is the nature of the cellular interactions involved?

If the etiology of myopia is related to a feedback mechanism that controls normal eye growth, it becomes important to understand what aspect of the visual image signals the eye to elongate and thereby become myopic. Over the next 5 years, it will be important to determine how many distinct mechanisms of experimentally induced refractive errors exist. The realization that myopia or hyperopia can develop to compensate for defocus imposed by spectacle lenses has created a controversy about whether these refractive changes are produced by the same mechanisms as the myopia resulting from visual deprivation. Resolving this controversy would add significantly to understanding the roles that defocus and other visual feedback play in emmetropization and the development of refractive error. The long-term goal is to learn what visual factors present in the environment may cause children to develop myopia.

Researchers anticipate that the next few years will see rapid progress in the identification of the signal cascades from retina to sclera that cause the eye to increase its rate of elongation, leading to myopia, or to decrease it, leading to hyperopia. Molecular biology techniques will be used to ascertain changes in expression of neurotransmitters, growth factors, and other regulatory proteins in experimentally induced myopia. Understanding these chemical signals may lead to pharmacological agents that might slow myopic progression.

Objective 1(b): Identify human risk factors for myopia and abnormal eye growth and evaluate promising treatments for preventing the onset of or slowing the progression of myopia, such as special spectacles or contact lenses or pharmacological treatments.

Research Needs and Opportunities

As knowledge of the underlying mechanisms that control eye growth and refractive compensation increases, the ability to assess the risk factors that predict the development of myopia in children or adults has increased as well. Reading is the most established risk factor for myopia. More recent observations have strengthened the association of the amount of near work with the rate of myopic progression.

Because the sharpness of the image during reading depends on the precision of accommodation, it is significant that myopic children have poorer accommodation than others. Additional research is needed into how accommodation and convergence are related to myopia. Researchers have also long suspected that genetic factors play a role in the cause of myopia. The evidence is especially strong in the case of pathological myopia (myopia of high degree). Refractive errors of monozygotic twins are more closely aligned than they are for dizygotic twins. A greater prevalence of myopia exists among the children of myopic parents than among the children of nonmyopic parents. Recent studies of the eye in infancy have also shown that the seeds of myopia may appear early in development. Longitudinal studies of refractive error have suggested that some myopic children may have previously been myopic as infants.

To make the transition from animal studies to clinical studies, there is a pressing need to determine how similar the biological mechanisms of eye growth are in different species, and how similar experimental models of myopia (by visual deprivation or the imposition of hyperopia by spectacle lenses) are to the myopia that develops in schoolchildren. Enough is presently known to begin to evaluate promising treatments for preventing the onset or slowing the progression of myopia and systematically investigate the risk factors associated with the development of myopia.

Strategic Research Questions

What interactions between heredity and environment result in myopia? During the next 5 years, researchers need to bring the biological side of myopia research to the point where the interactions of heredity and environment can be understood, as is beginning to occur with heart disease and obesity. One of the weaknesses of family studies is that it is difficult to separate out the contribution of genes in families from that of a shared environment. Do parents pass on to their children myopic genes or a love for reading? Statistical methods for examining the degree of interaction between heredity and near work should prove useful. These efforts will be strengthened by a genetic analysis of myopia, including linkage analysis or gene mapping. On the environmental side, increasingly sophisticated epidemiological surveys of refractive errors are needed to characterize better potential risk factors. Large-scale population surveys (such as the National Health and Nutrition Examination Survey) could include assessments of refractive errors. Ultimately, studies of visual, cell biological, genetic, and epidemiological factors will inform each other and lead to a better understanding of the etiology of myopia.

The clinical research community should also investigate a number of interesting research questions related to slowing the progression of myopia. Can progressive lenses or bifocals reduce myopic progression in children? Although researchers do not yet know what visual signal causes the retina to signal the eye to elongate, minimizing the blur that a child sees may reduce the impetus toward myopic growth. Can muscarinic agents prevent or reduce myopia? It has been shown in animals that muscarinic antagonists, such as atropine, reduce deprivation myopia, even in species in which these agents do not prevent accommodation. This has given a new rationale for this oldest preventive pharmacological treatment. What effect do rigid, gas-permeable contact lenses have on the progression of myopia? Given the results from some studies, a trial of rigid, gas-permeable contact lenses in children would seem worthwhile, taking into account how such factors as age, degree of myopia, corneal topography, and duration of contact lens wear affect myopia progression. Are there behavioral approaches that could be used to reduce myopia? A well-controlled test of "behavioral" methods of myopia control should be considered. Many patients are convinced that their myopic progression was slowed or reversed by various forms of vision training. If controlled studies confirmed this conviction, it would identify a treatment modality not presently taken seriously by most clinicians. If studies did not confirm it, patients might be deferred from unproved and unsound therapeutic practices. Any of these myopia treatments or prevention studies would be most logically performed in myopes or in children who have been identified to be at moderate to high risk for myopia. Risk-benefit ratios of treatment side effects versus the prevention of myopia will need to be evaluated in each of these studies, as will the reliability of each of the critical measures.

Objective 2(a): Investigate the effectiveness of immunomodulating therapies in halting disease progression in optic neuritis.

Research Needs and Opportunities

Optic neuritis results from inflammation or demyelination of the optic nerve and can lead to serious impairment of vision. Optic neuritis can represent an initial sign of a systemic neural disease such as multiple sclerosis (MS), or it can flare up locally for unknown reasons. It can occur at any stage of MS, but it is often the initial problem noticed by the patient in the early stages. The underlying mechanisms that cause optic neuritis are unknown, and knowledge has been scanty concerning the long-term natural history of the disease and the exact risk of MS associated with the disease. The Optic Neuritis Trial Treatment (ONTT) was the first multicenter trial sponsored by the NEI that yielded important advances in understanding this disease. The initial results, published in 1992, showed that the standard treatment of oral prednisone alone did not improve the visual outcome and was associated with an increased rate of new attacks of optic neuritis. Treatment with high-dose intravenous followed by oral corticosteroids accelerated visual recovery, but offered no long-term benefit to vision. This treatment produced a short-term reduction in the rate of development of clinically definite MS. This study also demonstrated that the presence of multiple enhancing lesions on the brain MRI scan performed at the time of optic neuritis diagnosis was the single most important predictor of the development of MS within 5 years. The probability of developing MS at 5 years ranged from 16 percent in patients with no lesions to 51 percent in patients with three or more lesions. Patients treated with high-dose methylprednisone had relative protection from developing MS for the first 3 years of followup, but at 5 years the protective effect was no longer observed.

Strategic Research Questions

Can a suitable animal model of optic neuritis be developed to help gain insight in the molecular mechanisms underlying the disease process? Lack of animal models for many neuro-ophthalmological diseases has hampered progress in understanding and treating these diseases. Thus, a very high priority should be the development of suitable, specific models for experimental investigation. Thus far, some insight has emerged from loosely related animal forms of disease, such as allergic encephalomyelitis and viral-induced demyelination. Can such models be used in devising immunomodulating therapies for optic neuritis? Studies of these models have suggested possible strategies to limit optic nerve damage from inflammation, and these need to be pursued. Immunomodulating therapies have shown great promise in slowing the progression of MS and therefore need to be assessed in optic neuritis.

Objective 2(b): Identify the unique characteristics of ocular muscles that render them vulnerable to Graves' ophthalmopathy, myasthenia gravis, orbital myositis, and chronic progressive external ophthalmoplegia.

Research Needs and Opportunities

Thyroid-associated ophthalmopathy (TAO) is a unique pattern of tissue remodeling in the eye orbit (including extensive inflammation and swelling) that is associated with Graves' disease. Graves' disease is an autoimmune condition with three defining symptoms: thyroid enlargement, thyroid overactivity, and a skin condition called dermopathy. Nearly 10 percent of Graves' patients also develop TAO that is severe enough to require treatment. Orbital tissues, including the extraocular muscles and fat, become inflamed, are infiltrated with lymphocytes, and accumulate hyaluronan, a complex carbohydrate. Over the past 5 years, the orbital fibroblast has been characterized extensively and shown to exhibit exaggerated responses to inflammatory signals such as cytokines. In addition, a key enzyme in the prostaglandin synthetic cascade is extremely inducible in orbital fibroblasts compared to many fibro-blasts from other regions of the body. The cytokine milieu in orbital tissues, which has been studied with immunohistochemical techniques, suggests the presence of factors such as interleukin-1 and tumor necrosis factor-alpha, which appear to mediate inflammatory responses. While these findings indicate that orbital tissue may be particularly susceptible to inflammation, the exact molecular events that initiate lymphocyte recruitment and activation are not understood, nor are the links between the thyroid disease and the pathology occurring in the eye orbit. This lack of insight severely limits the development of safe and effective therapeutic strategies for TAO.

Strategic Research Questions

In the field of autoimmune diseases of the eye orbit, of which TAO is a prominent example, what animal models could be used to study the molecular and cellular interactions between the immune system and the orbital connective tissue? High priority should be placed on studies that can yield insight into the initiating events leading to fibroblast activation and tissue remodeling and the cell signaling events that stimulate the trafficking of immunocompetent cells to the orbit. If possible, the common antigen shared by the thyroid and the orbit should be identified, as it would provide an important target for therapeutic drugs. Treatment strategies will need to be formulated and evaluated, initially in animal models and in vitro systems and ultimately in prospective in vivo studies. This will probably necessitate multicenter activities if the requisite numbers of subjects are to be included.

Objective 3: Discover how topographic gradients are generated and read out to form retino-topically ordered structures, and identify the sites and mechanisms of action of axon guidance molecules.

Research Needs and Opportunities

The increasing power and sophistication of molecular approaches over the past 5 years has led to an explosion of new information on the basic molecular mechanisms that guide the initial formation, connectivity, and topography of the visual system, and of the nervous system in general. Moreover, decades of investment in the study of the structure, function, and development of the visual system have made this the system of choice to study. The overriding opportunity for the next 5 years is to capitalize on recent advances to achieve a new, substantially more profound level of understanding of the molecular signals underlying both normal development and regeneration.

Strategic Research Questions

What are some of the molecular cues used in the developing visual system to guide growing axons and establish topographic connections? Elegant assays have shown that graded cell surface signals prevent retinal ganglion cell axons from innervating inappropriate regions of central targets. Subsequent studies in mammals have demonstrated that receptors and ligands belonging to the same class of molecules are organized into reciprocal gradients in the retina and tectum. Experiments show that the gradients that these molecules form can confer topographic specificity in the mammalian brain. While the existence of such gradients has been postulated for decades, scientists now have a firm handle on what types of molecules are involved in constructing such maps. The organization and function of these signaling pathways is likely to be a very rich area for exploration during the next 5 years.

This general approach has also led to the deciphering of some of the basic molecular codes regulating growth cone guidance and patterning of connections in the vertebrate nervous system. Almost 100 years after their existence was first postulated by Cajal, several members of a family of chemoattractant molecules, the netrins, were purified and cloned. These molecules are abundantly expressed in midline structures and, although first described in the spinal cord, are also present at crucial "choice points," such as the optic chiasm and the optic nerve head. Another class of secreted and membrane- bound guidance molecules, the semaphorins, are involved in the regulation of growth cones by both positive and negative actions. Members of this family induce growth cone collapse and are also likely to be involved in axon guidance. Both the netrins and the semaphorins are found in flies and worms. This discovery highlights the power of using a strategy of molecular homology in genetically tractable animals to identify important vertebrate signaling molecules and subsequently analyzing their functional roles in well-understood vertebrate systems, such as the visual system. From these molecular studies, the idea has emerged that negative regulators of axon guidance are probably at least as important as positive regulators. These different classes of molecules have both positive and negative roles. They are present in adults as well as during normal development, and they are likely to be important cues for determining the regenerative capacity of axon pathways.

High priority should be given to developing new assays that combine in vitro accessibility with increasing fidelity to the in vivo situation. The past 5 years have witnessed the first molecular insights into long-standing issues, such as the generation of topography within the visual system, but the present state of knowledge regarding the molecular determinants of development and regeneration remains rudimentary. The overriding opportunity for the next 5 years is to capitalize on these recent advances to reveal the molecular signals underlying both normal development and regeneration.

Objective 4: Determine the role of peptide growth factors, such as neurotrophins, in the development, plasticity, and regeneration of the visual pathways; determine how critical periods are regulated; manipulate the molecular signals underlying their regulation to enhance the adaptive and regenerative properties of the adult brain.

Research Needs and Opportunities

There is a pressing need to understand the exact mechanisms of action of known trophic molecules, such as the neurotrophins, which have clear potential as therapeutic agents in the regeneration and plasticity of the nervous system. Much work needs to be done on the functional roles played by these molecules and how their expression and efficacy are regulated by visual experience and activity. More studies are needed on their roles as survival and differentiation factors early in visual development.

Strategic Research Questions

What do researchers know about the molecular substrates governing the development and plasticity of the visual pathways? It is likely that the known molecules represent only the tip of an iceberg of similar molecules involved in regulating growth. Particularly promising approaches to discovering these molecules include cloning by homology and searching the ever-increasing set of known genetic sequences arising from the Human Genome Project and the Nematode Sequencing Project. In this context, large-scale screens of genetically modified organisms (such as flies and worms), with an eye toward molecules specifically involved in mammalian signaling pathways, are also likely to be a fruitful source of new insights. Another major advance in this area has been the discovery that the neurotrophin family of growth factors and the signaling pathways they utilize are likely to be key players in the control of brain plasticity. Although their precise roles are not established, adding or removing neurotrophins alters the normal formation of orientation and ocular dominance columns and responses to visual deprivation. Again, this is an area that opens up many therapeutic possibilities. The availability of powerful reagents to manipulate these growth factors should allow their roles to be rapidly identified. It is especially intriguing that the levels of neurotrophins are regulated by activity and the development of cortical dendrites and axons is influenced by the specific neurotrophins present at specific ages in the developing cortex.

Because of its accessibility and its relevance to restoration of vision, the optic nerve, which consists of the axons of retinal ganglion cells, is an especially tractable and appropriate model system for the study of the molecular basis of regeneration. Restoring function to the visual system is also easy to assess using electrophysiological, anatomical, and psychophysical techniques, and in many ways is less susceptible to the experimental limitations of other regeneration models such as the spinal cord. Nonetheless, it is almost certain that discoveries that reveal the molecular mechanisms mediating regeneration in the optic nerve will be of great importance elsewhere in CNS regeneration, particularly the spinal cord. Thus, special attention should be given to strategies that seek to identify the normal cues used to grow the optic nerve and to establish connections. These are likely to be useful in the context of regeneration. Additional effort should be invested in determining the molecular constraints in the adult nervous system that prevent axon growth and successful regeneration. The factors controlling neuronal growth are likely to be intimately involved in controlling the windows of time-critical periods when the structure and function of the visual system can be altered by visual experience. Researchers still lack a compelling explanation for the factors that produce closure of critical periods. This has been due in part to the limitations of pharmacological approaches. Developing new model systems, such as visual plasticity in knockout mice, should provide a powerful new tool to approach this issue, especially if expression of relevant genes can be manipulated in space and time.

Objective 5: Elucidate the mechanisms by which spontaneous patterns of electrical activity, present before the onset of visual experience, guide the formation of visual structures prior to visual experience.

Research Needs and Opportunities

In support of the idea that organized patterns of spontaneous activities play a crucial role in organizing the developing visual system, it is now clear that ocular dominance columns are present in adult-like form even in newborn monkeys. This implies that endogenous activity patterns are a powerful organizing force that operate well before vision is present and are sufficient to structure this important system. Recent work has demonstrated the presence of, and mechanisms underlying, spatiotemporally organized retinal waves in mammals and in turtles. These waves may be important not only for organizing the retinogeniculate and geniculocoritical pathways, but also for the development of the retina itself.

Strategic Research Questions

How do spontaneous patterns of activity guide the formation of visual pathways? Little is known about endogenous activity in sites other than the retina, and it is important to establish when such activity exists, whether it is patterned, and whether such patterns carry information necessary to appropriately wire the visual system. This will require the development of multisite recording capabilities in developing systems. With the advent of optical imaging of intrinsic signals, it has become possible to address the role of activity-dependent and nonactivity-dependent cues in the development of orientation selectivity in primary visual cortex. Using this approach, it is clear that organized maps of orientation preference are present prior to eye opening, suggesting that molecular cues or prenatal patterns of activity initially determine pattern orientation columns in the cortex. Single-unit electrophysiology, combined with pharmacological manipulations, suggest that cortical activity plays an important role in determining this property. Moreover, manipulating prenatal patterns of activity also prevent the normal emergence of well-tuned neurons, although the basic maps of orientation tuning are preserved. Understanding of intrinsic cortical circuit formation related to orientation tuning has also advanced significantly. The organization of lateral connections that link orientation columns are profoundly altered by both visual deprivation and other patterns of activity, but they can be established even in the absence of visual input. This implies that activity in other pathways, such as thalamocortical loops, may be providing important cues.

Objective 6: Characterize the clinical problems of amblyopia and impaired stereoscopic vision, and clarify their relationships to strabismus, anisometropia, and other related conditions.

Research Needs and Opportunities

Congenital and early-onset binocular imbalance, including strabismus, unilateral cataract, ptosis, anisometropia, and other unilateral conditions, affect the visual maturation of 3 percent to 5 percent of infants in the United States. Each of these conditions has the potential to cause both amblyopia and other abnormalities in binocular vision. Prevention or treatment of amblyopia through early diagnosis, optical correction, and occlusion therapy is often successful. Binocular sensory function is usually severely compromised by even brief periods of abnormal binocular experience during the first year of life.

Strategic Research Questions

How can researchers improve the visual outcomes for patients with early vision abnormalities? Several issues can only be resolved with rigorous observations of the natural history of these problems within the context of randomized clinical trials, but not on the basis of clinical records alone. Rigorous longitudinal trials of patient characteristics and treatment outcomes for different diseases would be extremely useful. Additional laboratory and clinical research is still needed to determine the etiology of strabismus. Scientists agree that some fraction of cases of strabismus arise from a primary motor anomaly, while others arise from a primary sensory anomaly. Different treatment approaches are clearly needed for different conditions, but there is no well-established agreement on the details for many conditions. In clinical studies, it is very important to concentrate on the two most important patient groups: infantile esotropes (who receive most surgical treatments), and accommodative esotropes (who receive a great deal of optical and orthoptic attention).

The etiology of infantile esotropia is still debated. While early surgical treatment may promote binocular function, it often fails to do so. Surgery may actually facilitate the development of amblyopia by converting the infant from alternating fixation to unilateral fixation, with constant suppression of central vision in the nonfixing eye. Systematic studies of patient characteristics and outcomes are needed. The etiology of accommodative esotropia is understood in terms of excess accommodative effort to overcome a high hyperopia that does not resolve. The question for these individuals is why they do not emmetropize in the usual way, and whether current strategies of refractive correction are appropriate or cause more long-term problems.

In addition to characterizing these patients and improving the outcomes of clinical trials of conventional treatments, clinical trials of noninvasive treatments (such as orthoptics and vision training) are needed to determine the presence of improvement in eye alignment and visual function. Recent evidence from experiments on cortical plasticity in animals suggests that even after the conventional period of plasticity, CNS function can be altered by patterns of use. What are the limits of neural plasticity in the adult? Experimental evidence documents occasional successes in ameliorating amblyopia in adults through training. Such work provides reason to suppose that some kinds of controlled visual practice regimes might be effective treatments, but these require convincing and systematic investigation under rigorous clinical research protocols.

Objective 7: Study the development and plasticity of neural mechanisms affected in strabismus and amblyopia, including studies in animal models and normal and abnormal human populations.

Research Needs and Opportunities

In parallel with more detailed studies of clinical populations, continued experimental work is needed to characterize the development and developmental plasticity of the specific neural mechanisms that are involved in strabismus and amblyopia. These include mechanisms of stereoscopic vision and visual sensitivity to pattern and form and the role of ocular proprioception.

Strategic Research Questions

How do various aspects of visual function mature in newborns? What is the normal development of eye movements, eye alignment, visual acuity (measured in different ways), color, motion, and depth perception? How does stereoscopic vision develop in normal subjects? In animals, how are cells that mediate stereoscopic perception organized? Which pathways and areas of the visual cortex are crucial for stereopsis? How do lesions in various portions of the visual pathways affect stereopsis? What defects (anatomical, physiological, and chemical) are seen in animals after misalignment of the visual axes?

Approaches to these issues include psychophysical studies of normal and abnormal human subjects and normal and abnormal behavioral and biological studies of the relevant neural circuits in experimental animals. An important goal for the next 5 years is to study mechanisms of binocular vision in normal and abnormal individuals. Binocular vision is easy to disrupt and difficult to restore after a period of abnormal visual experience, but the neural basis for these properties is unknown. Studies are needed in humans and animals that concentrate on the mechanisms of binocular interaction and binocular suppression, their development in early life, and their susceptibility to abnormal visual input.

Related experiments are also needed during the next 5 years in animal models of amblyopia. It is now well established that amblyopia can be created in animals by artificially producing several of the conditions thought to cause amblyopia in humans. But precise answers to a number of crucial questions are still needed. In general terms, what defects in cortical processing of retinal output are responsible for amblyopia? Early form deprivation causes shrinkage of ocular dominance columns in striate cortex and loss of cells responsive to the amblyopic eye. Work over the past 5 years has further characterized many changes that occur in striate cortex in both deprived animals and animals with other kinds of amblyopia, but very little is known about changes that occur in other regions of the visual cortex or how pathways between various cortical areas are affected in amblyopia. To answer these and related questions will require further use and refinement of animal models of amblyopia. It will also require continued study of these models using advanced techniques, detailed in earlier sections on the functional imaging techniques, to study the neural changes in human and experimental animal amblyopes and may in the long term be a technique of particular value.

Objective 8: Develop innovations in the detection and treatment of strabismus and amblyopia.

Research Needs and Opportunities

Researchers need to improve detection of refractive errors, strabismus, and amblyopia in infants and young children and, once detected, how to treat abnormalities for optimum improvement and avoidance of later problems. It is also important to learn what new diagnostic or surgical techniques for the evaluation or treatment of strabismus are most deserving of further study over the next 5 years.

Strategic Research Questions

Can better public health methods of testing visual function be developed for preverbal children? When children with visual abnormalities are identified, can better methods for detailed clinical office testing be developed? Photographic, video-based, and optoelectronic techniques are being developed for semiautomatic or automatic detection of refractive errors, strabismus, and amblyopia in infants and young children. These or other methods must be developed further to be cost-effective for mass screening. Thresholds must be established for detection of abnormalities, based on the benefits of detection. The effects of populationwide correction of mild or moderate refractive errors, for example, are not yet known, and may in fact be counterproductive by interfering with emmetropization. Proper studies of early intervention methods will be necessary to establish the benefits of early screening.

Automated eye-tracker-based measurement of strabismus in unrestrained children in free space and in different directions of gaze is a worthy goal for technology development. Measurement of fusional vergence potential and vergence amplitudes should also be automated. Surgical procedures, improved methods of botulinum toxin administration, and improved predictors of outcome are needed for common groups of patients, such as those with congenital esotropia, acquired esotropia, and deteriorated intermittent exotropia.

Objective 9: Develop fMRI and related technologies as useful, quantitative tools for exploring the neural basis of human visual processing.

Research Needs and Opportunities

The past 5 years have witnessed an impressive growth in the applicability of imaging technologies to the understanding of human brain function—and in visual function in particular. In the coming 5 years, developments in this area will provide new insight into the organization of brain areas involved in visual perception and in the control of visually guided behaviors. Because of its accessibility and science's large knowledge base, the visual system is already an important area of research in terms of imaging technologies and will undoubtedly continue to serve this role in the coming decades. In the realm of cortical processing, there is an urgent need to improve the spatial capabilities of existing imaging techniques. While optical imaging of intrinsic signals in animals has resolution on the spatial scale of single functional units (e.g., orientation columns), less invasive techniques, such as fMRI, which are much more suitable for use in humans, have not achieved comparable spatial resolution. Thus, an increase in spatial resolution of at least tenfold is required to extend the use of imaging technologies beyond localizing structures involved in various processes. In this case, the hurdles to be overcome are largely technical; attracting physicists, engineers, chemists, and investigators from other related disciplines will be necessary to overcome these technical obstacles. Considerably more work is also needed on understanding the relationship between functional MRI signals and neural activity. Currently, the source of the signals related to brain activity and their precise interpretations remains murky.

In the long term, researchers must consider developing novel, noninvasive techniques for electrically stimulating specific neural circuits within the human brain. Conceptually, progress in neurophysiology has rested on two legs: (1) being able to record, or "listen" to, the activity of nerve cells as they go about their business, and (2) being able to alter the activity of the same cells artificially (electrical stimulation) and observe accompanying changes in behavior. New imaging techniques are beginning to provide the capability to record neural activity in the human brain with useful spatial and temporal resolution. While transcranial magnetic stimulation holds some promise, radically new approaches will need to be developed, perhaps beginning in highly reduced preparations such as brain slices.

Strategic Research Questions

How can researchers best realize the vast potential of imaging technologies for exploring visual function? First, imaging of the human brain should be performed in parallel with similar studies in nonhuman primates, in which more invasive electrophysiological techniques can be used to confirm or expand findings from imaging studies. Combined imaging and electrophysiological analysis in experimental animals should also facilitate analysis of the actual physiological sources of the signals measured by fMRI. Imaging in nonhuman primates is in its infancy; much more work is needed in this area to allow data from animal experiments to inform those in humans.

Second, fMRI studies in humans should incorporate more rigorous experimental designs, borrowing liberally from the established methodologies of visual psychophysics. It is now clear that reliable fMRI signals can be obtained routinely and that, with additional effort, individual visual areas can be identified in individual human subjects. To exploit these new technical capabilities incisively, investigators must begin to draw on the insights and experimental designs of sensory psychophysics to pose concrete, answerable questions. It is likely that this combined approach holds the greatest potential for gaining novel insights into the neural basis of visual perception.

Third, substantial effort should be devoted to overcoming the current limitations of optical imaging techniques, the most important being limitations in the depth from which signals can be obtained. New techniques to allow areas buried in sulci to be visualized, ideally in awake, behaving animals, will provide insights into the function of brain areas that are currently poorly understood.

Finally, researchers should begin to develop new approaches for stimulating the brain noninvasively at a millimeter level.

Objective 10: Understand how neural computations are accomplished and stored within the central visual system.

Research Needs and Opportunities

At all levels of the visual system, from the retina through the cortex and including the brainstem nuclei involved in control of eye movements, there is an increasing recognition that local circuit processing holds the key to understanding how neural computations are accomplished and stored. Over the next 5 years, understanding how small groups of neurons interact to transform inputs and create behavioral outputs is likely to provide rich insights into the basic codes by which the mammalian brain functions. Investigations of such circuits have implications throughout the range of areas of interest to the SAVP Program, from the earliest stages of visual processing in the retina to the final stages of motor output at the extraocular muscles.

Strategic Research Questions

What new recording techniques, either optical or electrophysiological, can be used to probe activity patterns in small cell assemblies? Considerable effort is needed to develop new theoretical and practical tools for analyzing the voluminous data that will be obtained from such recordings. Progress is needed at several levels: developing new recording technologies, designing new signal processing algorithms, and forming new theoretical frameworks.

All circuits in the visual system on both the sensory processing and motor output branches show considerable plasticity on timescales, ranging from milliseconds to years. The next 5 years should be very rich in terms of understanding both the molecular and cellular bases of the various forms of plasticity and how plastic changes in neural circuits alter the capabilities of those circuits. Currently, most studies of cellular plasticity have concentrated on a restricted number of models and focused primarily on such phenomena as long-term potentiation and long-term depression. As new forms of plasticity emerge, understanding the circumstances under which the various forms are induced and the relationship between plasticity and long-term structural changes in neural circuits will soon increase in importance. Recent advances in video image processing, confocal microscopy (including multiphoton imaging), vital fluorescent dyes, and time lapse imaging may also be used in brain slices or intact brains to image structural changes in pre- and postsynaptic neuronal processes. This may help to determine what functional changes in visual synapses are actually associated with changes in the morphology of axon terminals or dendrites and the speed with which such changes can occur. At this time, plasticity studies generally focus on the level of single cells and individual synapses; increasing attention needs to be paid to the circuit level consequences of interactions between large numbers of synapses.

As more potential molecular candidates for mediating plasticity are uncovered, molecular genetic approaches need to be supplemented with more sophisticated analysis of signal transduction cascades involved in visual system plasticity. New cell fractionation procedures combined with physiologically relevant stimulation could be used to tease out the earliest events in many signal transduction cascades. Studies identifying important cytoplasmic pathways and distinguishing key posttranslational events and studies aimed at cloning early substrate proteins will be necessary to identify new targets for pharmaceutical development. These pharmaceuticals must be capable of reactivating synaptic plasticity and effective rewiring in the adult brain following childhood visual dysfunction or regeneration of axons following brain trauma. It is also important to determine whether new proteins are synthesized locally to produce synaptic change. More effort should be focused on identifying transcripts localized in dendrites, which could be locally produced during periods of high or curtailed plasticity.

Objective 11: Understand plastic mechanisms in the oculomotor system that ensure accurate gaze shifts, precise alignment of the two eyes, steady fixation that can be affected by nystagmus, and a stable visual world during self-movement.

Research Needs and Opportunities

Eye movement plays a key role in vision. Vision is blurred if the images of objects on the retina move more than a few degrees per second, as could happen during any movement of the head or body. Fortunately, the nervous system contains gaze stabilization mechanisms (chiefly the vestibulo-ocular and optokinetic systems) that move the eyes precisely to compensate for self-motion. Defects in these stabilization mechanisms lead to markedly reduced visual acuity, mislocalization of objects, and dizziness. Many cases of nystagmus, an uncontrollable back-and-forth movement of the eyes that afflicts many children and adults, can be traced to malfunctions of these stabilization mechanisms. The vestibulo-ocular reflex is primarily responsible for compensating for rapid head movements that would otherwise lead to blurred vision. Most studies of this reflex have been done by fixing the subjects' head rigidly and using a motor to move the head and body passively, as in a rotating chair. It was recently discovered, however, that many neurons in the vestibular system that carry a signal of head velocity during passive rotations of the head or body are silent during voluntary movements of the head (even though the head may be moving at a high velocity). The activity of these neurons is not simply suppressed during voluntary movements, however, because the neurons can still signal the occurrence of passive movement that is superimposed by an experimenter on an ongoing voluntary movement. This indicates that gaze stabilization during voluntary head movements is based on a complex computation that can distinguish between voluntary and passive movements of the head. Remarkably, even the responses of second-order vestibular neurons to head movement appear to be exquisitely sensitive to the behavioral context in which the movement is made. A clear need has emerged to analyze these gaze stabilization systems in a more natural environment, where voluntary and passive head movements may occur in any combination. The stabilization systems are much more complex than researchers recognized earlier.

A great deal of effort has been devoted in recent years to understanding the role of eye and head movements in the computations required to localize an object in space. There is no one-to-one relationship between which region of the retina is active and the location of an object in space. Light reflected from a stationary object can activate nearly any region of the retina, depending on where the eyes and the head are pointing. Thus, information about the site of retinal activity must be combined with information about eye and head position in order to look to or reach for objects of interest. Considerable progress has been made in understanding the role of the parietal and frontal cortices in these computations. Again, these findings indicate that researchers need to analyze the functioning of these systems in more natural situations, in which animals may look to or reach for a stationary object from any number of starting positions.

Strategic Research Questions

How are the eyes stabilized when a subject is free to move its head and body? In primate experiments, animals will need to be trained to make head, eye, and combined head and eye movements on command to assure proper experimental control. These experiments will be technically difficult but should answer important questions about how the vestibulo-ocular reflex is altered with actively generated eye and head movements. Although findings from these experiments will introduce new complexities of interpretation, experiments at this level are clearly necessary. Other oculomotor systems also need to be studied in a more natural or realistic setting, while still maintaining appropriate experimental control. We rarely shift our gaze without moving our heads; we seldom make a vergence eye movement without also making a saccade. Nonetheless, most studies have used highly restrictive procedures to isolate a particular function.

Recent research has provided far more insightful findings when these systems are studied under more realistic conditions. When saccades occur in conjunction with vergence movements, for example, vergence is speeded while saccades may be slowed. Thus, future studies should involve more natural motor activities, such as active head movement combined with saccades, pursuit, and vergence movements. Better integration between studies of the visual and oculomotor systems is another need. The human oculomotor control system and the visual system evolved together; indeed, the sole function of the oculomotor system is to facilitate good vision. In the past, visual system neurophysiologists have been primarily concerned with preventing eye movements during their experiments. Now there is a growing realization that an adequate description of the visual system must allow for the effects of eye movements. The effects of eye movements will have to be considered if researchers are to discover how to have a coherent view of the world in the face of nearly continuous eye, head, and body movement.

Objective 12: Extend studies of eye alignment to include vertical and torsional eye movement control; gain insight into the pathogenesis of cyclovertical strabismus.

Research Needs and Opportunities

Very precise movements of the eyes are required to maintain proper eye alignment when we shift our gaze between objects that are at different distances from us. Vergence eye movements and accommodation are mechanisms that maintain proper eye alignment and focus so that double vision (diplopia) and blurred vision are avoided. Misalignment of the two eyes, or strabismus, is an extremely common problem, affecting 3 percent to 5 percent of the population. Although there have been significant advances in understanding the basic neural circuits that control the movements of the eyes, the neural circuits involved in stabilizing retinal images by torsional rotations of the eyes—rotations of the eye along the line of sight—are poorly understood. Humans are usually unaware of these torsional movements, but in cases of congenital strabismus, or as a consequence of muscle palsies, the mechanisms that automatically adjust ocular torsion often break down. Single neuron recording experiments and reversible inactivation experiments have permitted identification of some neural systems in the midbrain that govern torsional movements. Much more work is needed, however, to understand how this important class of eye movements is produced and how these movements become defective during disease. Understanding the mechanisms that underlie the perception of the orientation of objects around the line of sight is also needed. A clearer understanding of how orbital connective tissue affects the movement of extraocular muscles is also important for the evaluation of strabismus and the consequences of strabismus surgery.

Strategic Research Questions

Binocular single vision requires that the two eyes be aligned properly with regard to the horizontal, vertical, and torsional axes of movement. Most work has focused on horizontal disjunctive movements, which may represent a special case because of the association with viewing distance and ocular accommodation. A crucial remaining question is: What are the mechanisms for establishing and maintaining eye alignment in all three axes? Answering the question poses a number of technical difficulties, although the search coil technique does provide a good means of measuring horizontal, vertical, and torsional movements in animals and cooperative subjects. Alternative eye movement recording techniques should be developed for patients and subjects who cannot use the search coil. A good biomechanical model of the eye that incorporates the latest findings on muscle pulleys, including data from imaging studies, is needed to understand how the central motor commands actually govern eye movement and eye alignment and how the ocular muscles interact to produce accurate, stable gaze.

Objective 13: Discover how visual information contributes to perceptual decisions, object recognition, internal representations of external space, transformations between different spatial frames of reference, and the formation of neural signals appropriate for guiding behavior.

Research Needs and Opportunities

Four decades of research into the central visual system, sponsored largely by the NEI, have now created strategic opportunities for neurobiological investigation of cognitive processes that are based on visual information. Scientists now have some degree of understanding of the way that information is extracted from the retinal image and stored in early areas of cerebral cortex, as well as insight into the organization of processing pathways in higher visual areas of the cortex. They are now in a position to ask considerably more sophisticated questions about how the brain makes decisions on the basis of visual information, how it recognizes objects, how it creates an internal model of external space, how it shifts visual information about the world from one spatial frame of reference to another, and how these cognitive processes ultimately generate signals appropriate for generating behavior.

Strategic Research Questions

How does the brain recognize objects in the visual world? How does it form decisions on the basis of incomplete evidence? How does it maintain an accurate representation of spatial relationships among objects in the world?

Despite variation in the visual image produced by changes in lighting or viewpoint, humans can generally identify familiar objects from many perspectives. The brain is not likely to store detailed three-dimensional representations of the vast numbers of objects that can be recognized by a single person, suggesting that the brain must employ an efficient compression system to store object representations in visual memory. A high research priority is to use both psychophysical and physiological tools to understand how this information compression is accomplished as visual data are processed within the hierarchy of cortical visual areas. Computational scientists have proposed iterative models of object recognition that are fairly successful in machine vision. These models use interactions between stored prototypes and incoming data to improve recognition. It is important to determine whether a similar strategy is employed in biological visual systems. Does feedback from stored information in the human cortex affect information acquisition during early stages of visual processing? Behavioral studies that use traditional psychophysical procedures should test whether these computational models are appropriate for human vision; fMRI measurements of human and monkey visual cortex during performance of object recognition tasks should provide additional data on cortical information flow and storage; and neurophysiological studies on single units should examine how neurons encode distinctive attributes that permit object recognition under a variety of viewing conditions. These diverse experimental approaches could provide information that will assist in diagnosing and treating stroke victims who are impaired in their ability to recognize objects.

Simple forms of decisionmaking can be investigated in animals that are trained to perform forced-choice discrimination tasks. Researchers need to understand how high-level neural circuits use basic sensory signals to form decisions which, in turn, guide behavioral responses. One approach to this problem is to require animals to make decisions near psychophysical threshold, where the sensory evidence is uncertain. Recording at successive levels of sensory processing pathways should allow researchers to determine where and how signals arise that are related unambiguously to the animal's choice rather than to any specific aspect of the stimulus itself. Psychophysicists and cognitive psychologists can contribute to this effort by designing behavioral paradigms that manipulate performance at the level of decisionmaking rather than the level of sensory processing. A promising example of this type of manipulation is the phenomenon of probability matching, where decisions are influenced not only by the present sensory stimulus but also by the animal's recent history of choice and reward. Neural signals that reflect this history are far more likely to participate in the decision process per se than in sensory representation.

The twin issues of spatial representation and coordinate transformation within the central visual pathways are the subject of vigorous investigation and are eminently deserving of continued study. We use our vision to judge the location, size, shape, and future position of objects in our surroundings. Information about these object properties arrives at the retina and is therefore initially represented in a retinal coordinate frame. To interact (grasp, catch, move toward, etc.) with such objects, however, the visual information picked up at the retina must be represented in a coordinate frame that is relevant to the muscles in the arms, legs, and hands. Recent psychophysical studies of human observers have shown that visual and nonvisual signals are used to make the coordinate transformations needed to perceive object position with respect to the body. Recent neurophysiological studies of the extrastriate cortex suggest that there are a number of intermediate representations of space between the visual input and the motor output. These intermediate representations are formed in some instances by modulating responses within a retinally defined receptive field by eye, head, or limb position. In other instances, however, visual receptive fields may actually move in accordance within the movement of the limbs. Much more research needs to be conducted with awake animals so that visual responses can be examined quantitatively during systematic manipulation of eye, head, and limb positions.

Objective 14: Understand the cellular mechanisms that give rise to changes in visual sensitivity associated with attention and perceptual learning.

Research Needs and Opportunities

Physiological work on visual attention has concentrated on exploring the effects of diverse behavioral paradigms on the signals carried by single neurons at successive stages of the central visual pathways. Attentional modulations of visual signals are more diverse and appear at earlier levels of the visual pathway than previously believed. Exploration and categorization of attentional phenomena at the neuronal level will undoubtedly continue, but new developments are needed in the circuit level analysis of visual attention. Scientists need to determine the cellular mechanisms that mediate the effects of visual attention within local neuronal circuits. It is also important to discover the source of the "control" signals that direct attention to or distract from particular features or locations in the visual environment. The role of feedback connections from higher cortical areas in implementing attentional modulation of sensory processing must also be investigated.

The field of perceptual learning is ripe for physiological investigation. Perhaps the most surprising insight gained from behavioral studies is that the performance gains associated with learning can be remarkably specific for the location in visual space and the exact stimuli for which the subject is trained. Counterintuitively, performance gains do not transfer easily to nearby regions of space or to closely related visual stimuli outside the training set. Some psychophysicists have interpreted this evidence to indicate that the neural changes caused by training are localized to very early stages of the cortical pathway. It is equally possible, however, that the neural changes occur in later stages that read out information from the early stages. The important question here relates to determining the neural mechanisms underlying practice-related gains in basic visual capacities. In principle, considerable insight into this issue can be gained from physiological recordings in trained animals.

Strategic Research Questions

What are the neural mechanisms underlying visual attention and perceptual learning? In the field of visual attention, it would be very useful to develop two or three model paradigms for extended physiological analysis. An ideal paradigm would include straight-forward, reliable behavioral methods for controlling attention in nonhuman primates and a visual area (or areas) in which neurons show robust response modulations that correlate with behavioral manipulations of attention. Pharmacological or thermal inactivation studies could determine whether that visual area contributes causally to attentional behavior. Inactivation of higher cortical areas, in concert with electrophysiological recording in the target area, could begin to provide insight into the sources of attentional control signals. Similarly, multiple electrode recordings may provide insight into interactions between cortical areas underlying attentional phenomena.

In the field of perceptual learning, high priority should be given to studies that promise physiological insight into the loci and mechanisms of learning phenomena. Most perceptual learning paradigms established by psychophysicists in the past few years have involved training periods lasting several days or weeks. Physiological analysis is likely to be most incisive if recording electrodes can be chronically implanted in targeted cortical areas while monkeys undergo training regimes similar to those used with humans. Care must be taken to create an experimental situation in which the neurons studied are most likely to contribute to the behavioral phenomena under analysis. For example, disparity-selective neurons might be the best candidates for physiological analysis of learning phenomena involving stereopsis.

STRABISMUS, AMBLYOPIA, AND VISUAL PROCESSING PANEL

CHAIRPERSONS

Lawrence Katz, Ph.D.
Duke University
Durham, NC

William Newsome, Ph.D.
Stanford University Stanford, CA

PANEL MEMBERS

Thomas D. Albright, Ph.D.
The Salk Institute
San Diego, CA

Martin Banks, Ph.D.
University of California School of Optometry
Berkeley, CA

Barbara A. Barres, M.D., Ph.D.
Stanford University School of Medicine
Stanford, CA

David L. Guyton, M.D.
Johns Hopkins University School of Medicine
Baltimore, MD

Jonathan Horton, M.D., Ph.D.
University of California
San Francisco, CA

Howard Howland, Ph.D.
Cornell University
Ithaca, NY

Shalom Kelman, M.D.
University of Maryland School of Medicine
Baltimore, MD

Peter Lennie, Ph.D.
University of Rochester
Rochester, NY

Dennis Levi, O.D., Ph.D.
University of Houston College of Optometry
Houston, TX

Stephen Lisberger, Ph.D.
University of California
San Francisco, CA

Lawrence Mays, Ph.D.
University of Alabama
Birmingham, AL

Suzanne McKee, Ph.D.
Smith-Kettlewell Eye Research Institute
San Francisco, CA

Carlos Moraes, Ph.D.
University of Miami
Miami, FL

J. Anthony Movshon, Ph.D.
New York University
New York, NY

Don Mutti, O.D., Ph.D.
University of California, Berkeley
Berkeley, CA

Anthony M. Norcia, Ph.D.
Smith-Kettlewell Eye Research Institute
San Francisco, CA

Martha Constantine-Paton, Ph.D.
Yale University
New Haven, CT

Terry Smith, M.D.
Albany Medical College
Albany, NY

David Sparks, Ph.D.
University of Pennsylvania
Philadelphia, PA

Joshua Wallman, Ph.D.
The City College of New York
New York, NY

Terri Young, M.D.
University of Minnesota
Minneapolis, MN

Karla Zadnik, O.D., Ph.D.
The Ohio State University
Columbus, OH

NEI STAFF

Michael D. Oberdorfer, Ph.D.
National Eye Institute, NIH
Bethesda, MD


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