Presbyopia is a condition in which the natural aging of the eye results in a loss of accommodation. This loss in functionality is accompanied by a decrease in the compensatory mechanism between the aberrations of the cornea and lens. The result is a decrease in image quality and ability to focus on near objects.

Spherical aberrations (SA) inherently produce a depth of focus (DOF) when they exist in an optical system. Presented here is a theoretical analysis of the application of higher order SAs to the ocular optical systems of presbyopic subjects in order to provide DOF. Proposed SAs were tested in a small pre-presbyopic subject group to evaluate the effectiveness of the aberration interactions in providing enhanced through focus image quality.

Primary and secondary SAs were found to have a linear relationship with defocus in optimizing image quality. When primary SA was 1/3 the value of defocus, or secondary SA was 1/2 the value of defocus optimal image quality was measured as a peak in the visual Strehl ratio based on the optical transfer function. Adequate DOF can be achieved with varying levels of higher order SA. Combining the primary and secondary SA with in the optical system also functionally increases the DOF while allowing for a reduction in the magnitude of the SA terms used. When tested with higher order SA values chosen to optimize viewing for 50cm (2D), all four subjects reported an increase in DOF in addition to a slight decrease in visual acuity as predicted.

Other factors such as decentration, chromatic aberration and the Stiles-Crawford effect had little impact on the induced DOF achievable with SA. The image quality reduction was minimal with these factors; however the greatest impact in DOF and image quality was produced with large amounts of corneal aberrations such as astigmatism and coma.

A trade off exists between the DOF and image quality achievable, therefore SA terms must be chosen in order to minimize the negative effects of each. The analysis presented here provides a basis for further investigation and optimization of higher order aberration interactions for customized presbyopic corrections.

Action video game playing has been shown to significantly improve reaction times and modify selective visual attention, from the spatial distribution and resolution of attention to the temporal characteristics of attention and its capacity. However, two important questions are still unresolved. One is whether the beneficial effects of action video game playing can generalize to basic functions of low level vision, and if so through which mechanism(s) action video game playing may be doing this. Here we designed a series of experiments to investigate these two fundamental questions.

In the first experiment, the contrast sensitivity function, which is one of the main determinants of how well a people can see, of action video game players (VGPs) and non action video game players (NVGPs)' were measured through a contrast detection task. VGPs showed over all improved contrast sensitivity in comparison to NVGPs, especially at middle and high spatial frequencies. VGPs also showed faster temporal integration time in contrast detection. These results suggested that action video game playing is able to modify one of the most fundamental properties of vision. In the second experiment, we investigated whether the effects of action video game playing can generalize to basic temporal visual functions. We measured the visual masking effect in VGPs and NVGPs. VGPs showed reduced backward masking effect in comparison to NVGPs, while leaving forward masking effect intact. This result confirmed the role of action video game playing in modifying low level vision and also suggested that VGPs have a faster temporal resolution of visual processing.

Importantly, the causal effect of action video game playing on contrast sensitivity and visual masking was established through intensive 50 hours of video game training studies in NVGPs. In the third experiment, a perceptual template model (PTM) developed by Dosher and Lu (1998) was used to assess the mechanisms underlying action video game playing. VGPs showed lower contrast thresholds for an orientation identification task across all external noise levels. Through PTM, VGPs' superior performance can be captured by two mechanisms: 1) internal additive noise reduction and 2) external noise exclusion, reflecting channels reweighing at the cortical level. A training study then established the causal effect of action video game playing in this enhancement. This result suggested that when faced with a new task or environment, action game experience allowed the participant to reselect and/or strengthen taskrelated channels, as well as reduce irrelevant channels, to process visual information more efficiently. This proposed hypothesis naturally explained the greater efficiency of VGPs in performing cognitive and perceptual tasks and how the improvements generalized to untrained conditions.

There is growing evidence on the dynamic plastic nature of the human brain across the lifespan. Neurons are highly specialized structures, resistant to change, but engaged in circuits and distributed networks that do dynamically change over the lifespan. Changes in functional connectivity, for example by shifts in synaptic strength, can be followed by more stable structural changes. Therefore, the brain is continuously undergoing plastic remodeling.

Plasticity is not an occasional state of the nervous system, but the normal ongoing state of the nervous system throughout the life span. It is not possible to understand normal psychological function nor the manifestations or consequences of disease without invoking the concept of brain plasticity. Furthermore, the mechanisms of plasticity themselves may be aberrant and pathogentically contribute to the manifestation of disease.

The challenge is to understand the mechanisms and consequences of plasticity in order to modulate them, suppressing some and enhancing others, to promote adaptive brain changes and the most desirable outcome for a given individual.

Understanding the mechanisms and substrates for neural circuit retraining would be of great value for designing new and refining existing clinical strategies used to treat neurological, neurodevelopmental, addictive, psychiatric, developmental and aging disorders. Plasticity-based interventions and retraining to restore or improve function might have profound impacts on central nervous system (CNS) disorders as diverse as traumatic brain and spinal cord injury, stroke, Alzheimer's disease, Parkinson¹s disease and other degenerative disorders, addiction, neuropsychiatric disorders, such as schizophrenia or depression, and developmental disorders, such as autism.

Proper functioning of the nervous system requires the formation and maintenance of precise connectivity patterns between neurons. Our laboratory focuses on developmental mechanisms that regulate precision in circuit assembly of retinal neurons. Using live-cell imaging approaches to visualize retinal synaptogenesis under normal or perturbed developmental conditions, we have uncovered unexpected strategies by which neurons establish their mature connectivity patterns.

The adrenergic and cholinergic systems play a crucial role in subordinating neural plasticity, including learning and memory, to the individual's behavioral state. Most of our understanding of the action of these neuromodulators on plasticity derives from their effects on membrane excitability and neurotransmitter release. Thus, it is well accepted that by controlling neural activity, the neuromodulators can facilitate or restrict the recruitment of activity dependent forms of plasticity such as LTP and LTD. I will discuss results obtained in the visual cortex indicating that rather that being simple modifiers of plasticity, adrenergic and cholinergic receptors determine the polarity of plasticity (whether LTP or LTD). This property can be exploited to potentiate or depress synapses in vivo in a controlled manner.

The resolution of an imaging system is limited by the wavelength and numerical aperture of the system. Structured illumination imaging has been applied in microscopy to resolve spatial frequencies that conventionally lie outside the passband of the imaging system. The object is imaged with a sinusoidally patterned illumination, rather than the customary uniform illumination. This produces aliased moiré patterns which carry high frequency information in the image. These aliasing effects shift the traditionally inaccessible portions of the object's spatial frequencies into the passband of the system making superresolution imaging possible. Structured illumination has also been used to obtain axially sectioned images on similar lines as the superresolution imaging with somewhat modified image processing.

The applications of interest in this thesis are ophthalmoscopy and any moving microscopy application. The human retina is made up of millions of cells. Imaging the human retina in vivo is necessary for the study of structure and function of retinal physiology, and the detection, diagnosis and study of retinal diseases. In vivo retinal imaging with adaptive optics has shown the potential to resolve individual cells non-invasively. Cells such as cones, blood vessels and retinal pigment epithelial cells can now be routinely imaged in the human retina in vivo. The resolution of adaptive optics retinal imaging systems is fundamentally limited by the size of the pupil of the eye. The pupil aperture cannot increase beyond a certain point even with dilating drops. This restricts retinal imaging to structures larger than about 2 microns. In order to image finer features such as rods, foveal cones, ganglion cell axons and dendrites, it is necessary to use superresolution imaging. Similar incentives and restrictions for imaging moving specimens makes superresolution attractive to other forms of microscopy as well.

However, prior work in the area of structured illumination imaging has been restricted to imaging stationary objects with fixed, known phase shifts in the sinusoidally patterned illumination. In this thesis we apply this technique to moving objects. We have modified existing theory and algorithms for structured illumination imaging to accommodate a randomly moving rigid, translating object, such as the human retina in vivo. We show results for phase shift estimation and superresolution in simulation as well as with experimental implementation on a microscope. Further this thesis also explores the implementation of this technique on a widefield, flood illuminated, adaptive optics retinal imaging system. It also addresses some aspects of speckle reduction and image registration for the coherent laser illumination of a moving in vivo retina.

Since many structures in the retina and in microscopy are non-fluorescent, this thesis also explores the coherent case for structured illumination imaging using a laser illumination for non-fluorescent objects. We expand the scope of the theory and algorithms to account for coherence and associated speckle and other artifacts. We show simulation results for this aspect of the project.

We also investigate the application of axial sectioning using structured illumination for moving fluorescent objects. We prove the results for this portion of the thesis using fluorescence images on a microscope.

Orienting to objects in our environment is a ubiquitous behavior that enables us to extract high quality visual information about our world, helps us navigate through complex environments and contributes to our daily interactions. Understanding the neural mechanisms that form the basis for these common activities requires development of ways in which to separate individual movement components in order to correlate neural activity with some but not other features, and also a recognition that naturally occurring movements are made within a broader context. I will describe ongoing projects in the lab including what impact head movements have on saccadic eye movements, how this alters hypotheses of gaze shift control, and the role of brainstem centers (superior colliculus et al.) in producing these coordinated movements.

Damage to the adult primary visual cortex (V1) causes a loss of conscious vision over the same part of the visual field in both eyes (cortical blindness). It represents an increasingly common and significant cause of permanent disability in older humans. Cortical blindness hinders every aspect of an individual's daily life, including reading, navigating, and driving. Part of the research in our lab focuses on using immersive virtual reality technology to characterize how loss of a large portion of the peripheral visual field affects visual function in dynamic, naturalistic circumstances. In particular, we are interested in defining how quickly and under what circumstances cortically blind subjects acquire compensatory eye movement strategies to help them deal with their vision loss. A second area of interest is to understand how visual training may improve visual perception in cortically-blind fields. Though some still believe visual rehabilitation to be clinically unfeasible, the presence of residual visual processing abilities in cortically blind fields (commonly known as 'blindsight') suggests a possibility of vision recovery though perceptual training. Our results confirm this suggestion by showing that the discrimination of moving or flickering visual targets in cortically blind fields can be retrained back to normal levels. However, the mechanisms and pathways underlying such training-induced recovery remain uncertain. Preliminary psychophysical data suggest that training-induced visual recovery in cortically blind fields can occur for stimulus conditions that do not normally elicit blindsight. Furthermore, unlike blindsight, which is though to be mediated by sub-cortical projections to extrastriate motion-processing areas (esp. hMT+), fMRI shows training-induced visual recovery in cortically blind fields to be associated with the re-activation of the canonical route of visual information transfer in the brain, involving intact areas at both lower and higher levels of the visual system. This may explain the broader than normal generalization of learning observed in cortically blind fields and suggests new directions for the development of better rehabilitation strategies for patients with cortical blindness.

Glaucomas are a complex and diverse group of diseases that often lead to blindness. They are unified by the characteristic cell death of the output neuron of the retina, the retinal ganglion cell (RGC). To date, the primary insult and molecular signaling pathway(s) responsible for RGC death in glaucoma are undefined. What is clear is that degenerating RGCs exhibit chromatin condensation, nuclear fragmentation and other hallmarks of apoptotic cell death. Even more importantly, it is known that the pro-apoptotic molecule BAX is required to initiate apoptosis in response to glaucomatous insults to RGCs. BAX is the downstream executor of a family of molecules - the Bcl-2 family - known to integrate pro-survival and pro-death cell signaling pathways and ultimately determine an injured cell's fate. Individual Bcl-2 family members are sensitive to specific insults, including insults hypothesized to play a role in glaucoma, such as the loss of neurotrophic support. However, in RGCs the specific Bcl-2 family members controlling BAX are not known. The requirement for BAX activation in RGC apoptosis provides a starting point for unraveling the complex process that determines RGC survival in glaucoma. Our hypothesis is that RGC death represents the ability of glaucomatous insults to alter the profile of Bcl-2 family member interactions in RGCs in favor of BAX activation. Therefore, as the first step toward revealiglaucoma, our immediatmembers in RGC death.

Most human activities are a mixture of cognitive, perceptual, and motor processes. These processes rarely operate in an independent fashion, but are instead tightly integrated and coordinated in order to efficiently achieve our goals. In our daily lives, we must often think and plan while concurrently acting, and given the limits of our perceptual systems, we must sequentially allocate visual gaze across numerous activities that require visual attention. While much is known about our perceptual and motor systems operating in isolation, much less is known about the control mechanisms that coordinate cognition, perception, and motor control in naturalistic tasks. In this talk I will focus on a particular facet of this coordination problem. In particular, I will examine how the timing of eye movements is strategically controlled to share visual gaze among two competing activities: vision for online motor control, and information acquisition to support the planning of future actions. Beyond showing empirically that subjects alter the timing of their eye movements to the demands of the task environment, I will describe a computational model (based on stochastic optimal feedback control theory) that predicts the optimal allocation of visual gaze in this task. The model results demonstrate that humans are able to adapt their eye movement behavior to the demands of a task environment, and perhaps surprisingly, do so in a nearly optimal manner.

An emerging field in functional retinal imaging has been the investigation of intrinsic optical reflectance signals in the retina. Specifically, the intrinsic signals we have studied are changes in near infrared (NIR) reflectance in response to patterned visual stimulation. The NIR response shows tight colocalization with the stimulated region of retina. The strong colocalization in particular holds great appeal because it suggests a local mechanism of action, which may be used to assess conditions of retinal health with high spatial resolution across a wide field of view. Our research has focused on elucidating the biophysical and anatomical origins of these novel intrinsic signals.

Method. A modified fundus camera (Topcon) was used to simultaneously stimulate and optically record from the ocular fundus of anesthetized cats and monkeys. A diffuse NIR light (700-900 nm) served as the interrogation energy while keeping the eye in a dark-adapted state. NIR signals were evoked by visual stimulation with patterned visible stimuli (540 nm, 2-7 cd/m2). Optical reflectance was captured with a cooled CCD camera (Photometrics) in the NIR range. Adaptations of this basic paradigm allowed us to examine the spatial, spectral and temporal properties of the intrinsic signals. Here, I present several key findings that help identify the origins of the signals. 1. Characterization of the spatio-temporal properties reveals two dominant signals in the retina, a negative signal corresponding to a relative decrease in reflectance and an adjacent positive signal corresponding to an increase in reflectance. 2. Imaging wavelength dependence reveals signals are greatest at the shorter end of the NIR spectrum consistent with a hemodynamic origin. However, signal polarity does not flip at the oximetry isosbestic wavelength 800 nm, meaning signals cannot be purely of oximetric origin. 3. Systemic injections of blood contrast agents indocyanine green (ICG) and nigrosin increase the magnitude of the signals. This result suggests functional contrast is provided by stimulus-evoked changes in blood volume. 4. Pharmacological blockade using L-2-amino-4-phosphonobutyric acid (APB), cis-2,3 piperidine dicarboxylic acid (PDA) or the sodium channel blocker tetrodotoxin (TTX), did not appreciably diminish the magnitude, spatial characteristics or time course of the intrinsic signals suggesting signals arise from an outer retinal origin. 5. Signal properties were further examined in a Siamese cat model of human glaucoma. Cats with congenital, open-angle glaucoma showed chronically elevated intraocular pressure and retinal nerve fiber layer thinning. Intrinsic signals persisted in these animals despite anatomical and functional ganglion cell loss. These findings are consistent with a minimal contribution from ganglion cells.

Taken together, the bulk of this research has: A) Established the properties of the signals important for future investigations. B) Provides a functional basis of the signal origin in stimulus-evoked changes in blood volume. C) Demonstrates inner retinal function is not the dominant origin of the signal.

Successfully interacting with our environment requires the balancing of top-down control attentional control with reflexive attentional capture. A long standing assumption has been that the human reflexive attention system has evolved over generations to prioritize those visual events that confer some advantage in survival to the observers. To examine this assumption, I will present two lines of research. The first will show that animate motion, the motion associated with the movement of biological entities (such as potential prey and predators), effectively captures our attention. The second will show that information about emotions, hypothesized by Darwin and others to have evolved from actions, captures attention and receives prioritized processing through the magnocellular visual pathway. Empirical support for the hypothesized evolutionary link between emotions and actions will also be presented.

What is the representation in early vision? Considerable research has demonstrated that the representation is not equally faithful throughout the visual field; representation appears to be coarser in peripheral and unattended vision, perhaps as a strategy for dealing with an information bottleneck in visual processing. In the last few years, a convergence of evidence has suggested that in peripheral and unattended regions, the information available consists of summary statistics. For a complex set of statistics, such a representation can provide a rich and detailed percept of many aspects of a visual scene. However, such a representation is also lossy; we would expect the inherent ambiguities and confusions to have profound implications for vision. For example, a complex pattern, viewed peripherally, might be poorly represented by its summary statistics, leading to the degraded recognition experienced under conditions of visual crowding. Difficult visual search might occur when summary statistics could not adequately discriminate between a target-present and distractor-only patch of the stimuli. Certain illusory percepts might arise from valid interpretations of the available lossy information. It is precisely visual tasks upon which a statistical representation has significant impact that provide the evidence for such a representation in early vision. I will summarize recent evidence that early vision computes summary statistics based upon such tasks.

Presbyopia, the age-related loss of unassisted near vision, is a visual affliction which significantly affects anyone beyond the age of 40 years. There are several clinically well-established techniques for correcting presbyopia, ranging from the ubiquitous bifocal spectacles to surgically implanted premium (multifocal and accommodating) intraocular lenses (IOLs). Many clinical studies have been carried out to determine the efficacy of premium IOLs, however their results are largely based on a subjective assessment of visual quality. An adaptive optics (AO) metrology system was developed to objectively assess through-focus image quality of the IOLs and to investigate the effects of uncorrected corneal astigmatism and higher order aberrations on their performance. We found that multifocal IOLs have an extended depth of focus, as compared to monofocal and accommodating IOLs, however they are sensitive to corneal aberrations. Another method for overcoming presbyopia is monovision. In traditional monovision, the patient's dominant eye is refracted for distant vision and the non-dominant is refracted for near vision. Poor intermediate image quality and monocular suppression of visual input can cause discomfort in presbyopic patients. We propose a modification to traditional monovision to improve through-focus visual performance by extending the depth of focus of each eye with spherical aberration. This method minimizes disparity in retinal image quality between two eyes, resulting in enhancing binocular summation rather than binocular suppression through focus. A recently developed binocular AO system was used to induce spherical aberrations in various combinations in both eyes and to measure through-focus binocular visual performance with the modified monovision.

Most organisms facing a choice between multiple stimuli will look repeatedly at them, presumably implementing a comparison process between the items' values. Little is known about the exact nature of the comparison process in value-based decision-making, or about the role that the visual fixations play in this process. We propose a computational model in which fixations guide the comparison process in simple binary value-based choice and test it using eye-tracking. We present results from an eye-tracking choice experiment showing that the model is able to quantitatively explain complex relationships between fixation patterns and choices, as well as several fixation-driven decision biases. We also present results from several fMRI choice experiments showing that the key processes at work in the model are implemented in the ventromedial and dorsomedial prefrontal cortices.

Treatments for retinal diseases that cause vision loss and blindness, such as diabetic retinopathy and age-related macular degeneration, could be more rapidly developed and evaluated if a patient's response to therapy could be predicted earlier in the course of the disease than is currently possible. Since 1992, Dr. Berkowitz's research has focused on the development and application of physiologically accurate magnetic resonance imaging biomarkers for evaluating how and when treatment efficacy is best achieved during emerging retinopathy. The most promising method can analytically and non-invasively measure retinal ionic regulation, including the dark current, using manganese-enhanced MRI (MEMRI). In preclinical models of retinopathy, well before the appearance of retinal lesions, we find significant changes in MEMRI patterns that respond well to treatment and which may represent new therapeutic targets for interventional therapy.

The structures involved in age-related macular disease are the choroid, Bruch's membrane retinal pigment epithelium (RPE), and photoreceptor cells. Changes in each represent a potential target for treatment.

Choriocapillaris: In young healthy individuals, the choriocapillaris is formed of a sinusoidal complex, which is fenestrated and lacks tight junctions. In one morphometric study, it was found that the density of the choriocapillaris decreases with age in eyes without AMD In another study, neoprene casts were used to show the change to a tubular vascular system from a sinusoidal system with age In advanced AMD, loss and narrowing of the choriocapillaris occurs. It is believed that the nature of the choriocapillaris is determined, in part, by the outward constitutive expression of VEGF by the RPE. The changes in the choroid may be due to intrinsic vascular disease or to failure of VEGF expression by RPE or blocking outward diffusion of VEGF from RPE.

Bruch's membrane: Many studies have shown that Bruch's membrane becomes thicker with age. It contains several proteins involved in the complement cascade suggesting that inflammation may play a role in causing cell death. Alternatively the proteins may be oligomerised such they no longer have the biological properties of the monomers. It also contains considerable quantities of lipid and represents a barrier to metabolic exchange between the choroid and RPE.

Retinal pigment epithelium: It has been recognised that the levels of lipofuscin increase with age. Lipofuscin is formed of ethanolamine and vitamin-A. Geographic atrophy is preceded by high levels of lipofuscin as determined clinically as hyperautofluorescence. Lipofuscin is a source of free radicals when exposed to short wavelength light. In addition it interferes with degradation of the phagosome thus reducing the amount of lipid that is available for photoreceptor outer segment renewal. The higher levels of geographic atrophy in Iceland when compared with the rest of Western Europe may be explained by the high intake of vitamin-A in Iceland.

Photoreceptor cells: Both clinical and histopathological studies imply that there is major loss of photoreceptor cells prior to loss of RPE during the evolution of geographic atrophy. It is also apparent that loss of rod photoreceptor cell is much more profound that loss of cones.

Non-linear microscopy techniques are becoming important tools in areas of medical and biological science. These techniques might be significantly improved when combined with adaptive optics (AO) reducing the required excitation power levels and minimizing phototoxicity side-effects. Some examples of the application of our AO non-linear microscope to different eye tissues (cornea and retina) will be presented.