Enhancing the Visualization of the Peripheral Retina with Wide Field-of-View Optical Coherence Tomography

The goal of my Ph.D. thesis is to enhance the visualization of the peripheral retina using wide-field optical coherence tomography (OCT) in a clinical setting.

OCT has gain widespread adoption in clinical ophthalmology due to its ability to visualize the diseases of the macula and central retina in three-dimensions, however, clinical OCT has a limited field-of-view of 300. There has been increasing interest to obtain high-resolution images outside of this narrow field-of-view, because three-dimensional imaging of the peripheral retina may prove to be important in the early detection of neurodegenerative diseases, such as Alzheimer's and dementia, and the monitoring of known ocular diseases, such as diabetic retinopathy, retinal vein occlusions, and choroid masses.

Before attempting to build a wide-field OCT system, we need to better understand the peripheral optics of the human eye. Shack-Hartmann wavefront sensors are commonly used tools for measuring the optical imperfections of the eye, but their acquisition speed is limited by their underlying camera hardware. The first aim of my thesis research is to create a fast method of ocular wavefront sensing such that we can measure the wavefront aberrations at numerous points across a wide visual field. In order to address aim one, we will develop a sparse Zernike reconstruction technique (SPARZER) that will enable Shack-Hartmann wavefront sensors to use as little as 1/10th of the data that would normally be required for an accurate wavefront reading. If less data needs to be acquired, then we can increase the speed at which wavefronts can be recorded.

For my second aim, we will create a sophisticated optical model that reproduces the measured aberrations of the human eye. If we know how the average eye's optics distort light, then we can engineer ophthalmic imaging systems that preemptively cancel inherent ocular aberrations. This invention will help the retinal imaging community to design systems that are capable of acquiring high resolution images across a wide visual field. The proposed model eye is also of interest to the field of vision science as it aids in the study of how anatomy affects visual performance in the peripheral retina.

Using the optical model from aim two, we will design and reduce to practice a clinical OCT system that is capable of imaging a large (800) field-of-view with enhanced visualization of the peripheral retina. A key aspect of this third and final aim is to make the imaging system compatible with standard clinical practices. To this end, we will incorporate sensorless adaptive optics in order to correct the inter- and intra- patient variability in ophthalmic aberrations. Sensorless adaptive optics will improve both the brightness (signal) and clarity (resolution) of features in the peripheral retina without affecting the size of the imaging system.

The proposed work should not only be a noteworthy contribution to the ophthalmic and engineering communities, but it should strengthen our existing collaborations with the Duke Eye Center by advancing their capability to diagnose pathologies of the peripheral retinal.

Dynamics of visual receptive fields in the macaque frontal eye field.

Neuronal receptive fields (RFs) provide the foundation for understanding systems-level sensory processing. In early visual areas, investigators have mapped RFs in detail using stochastic stimuli and sophisticated analytical approaches. Much less is known about RFs in prefrontal cortex. Visual stimuli used for mapping RFs in prefrontal cortex tend to cover a small range of spatial and temporal parameters, making it difficult to understand their role in visual processing. To address these shortcomings, we implemented a generalized linear model to measure the RFs of neurons in the macaque frontal eye field (FEF) in response to sparse, full-field stimuli. Our high-resolution, probabilistic approach tracked the evolution of RFs during passive fixation, and we validated our results against conventional measures. We found that FEF neurons exhibited a surprising level of sensitivity to stimuli presented as briefly as 10 ms or to multiple dots presented simultaneously, suggesting that FEF visual responses are more precise than previously appreciated. FEF RF spatial structures were largely maintained over time and between stimulus conditions. Our results demonstrate that the application of probabilistic RF mapping to FEF and similar association areas is an important tool for clarifying the neuronal mechanisms of cognition.

A subcortical source of visual input to the frontal eye field

Many neurons in the frontal eye field (FEF) exhibit visual responses and are thought to play important roles in visuosaccadic behavior. The FEF, however, is far removed from striate cortex. Where do the FEF's visual signals come from? Usually they are reasonably assumed to enter the FEF through afferents from extrastriate cortex. Here we show that, surprisingly, visual signals also enter the FEF through a subcortical route: a disynaptic, ascending pathway originating in the intermediate layers of the superior colliculus (SC). We recorded from identified neurons at all three stages of this pathway (n=30-40 in each sample): FEF recipient neurons, orthodromically activated from the SC; mediodorsal thalamus (MD) relay neurons, antidromically activated from FEF and orthodromically activated from SC; and SC source neurons, antidromically activated from MD. We studied the neurons while monkeys performed delayed saccade tasks designed to temporally resolve visual responses from presaccadic discharges. We found, first, that most neurons at every stage in the pathway had visual responses, presaccadic bursts, or both. Second, we found marked similarities between the SC source neurons and MD relay neurons: in both samples, about 15% of the neurons had only a visual response, 10% had only a presaccadic burst, and 75% had both. In contrast, FEF recipient neurons tended to be more visual in nature: 50% had only a visual response, none had only a presaccadic burst, and 50% had both a visual response and a presaccadic burst. This suggests that in addition to their subcortical inputs, these FEF neurons also receive other visual inputs, e.g. from extrastriate cortex. We conclude that visual activity in the FEF results not only from cortical afferents but also from subcortical inputs. Intriguingly, this implies that some of the visual signals in FEF are pre-processed by the SC.

The frontal eye field sends predictively remapped visual signals to the superior colliculus

We perceive a stable visual world even though saccades often move our retinas. One way the brain may achieve a stable visual percept is through predictive remapping of visual receptive fields: just before a saccade, the receptive field of many neurons moves from its current location ("current receptive field") to the location it is expected to occupy after the saccade ("future receptive field"). Goldberg and colleagues found such remapping in cortical areas, e.g. in the frontal eye field (FEF), as well as in the intermediate layers of the superior colliculus (SC). In the present study we investigated the source of the SC's remapped visual signals. Do some of them come from the FEF? We identified FEF neurons that project to the SC using antidromic stimulation. For neurons with a visual response, we tested whether the receptive field shifted just prior to making a saccade. Saccadic amplitudes were chosen to be as small as possible while clearly separating the current and future receptive fields; they ranged from 5-30 deg. in amplitude and were directed contraversively. The saccadic target was a small red spot. We probed visual responsiveness at the current and future receptive field locations using a white spot flashed at various times before or after the saccade. Predictive remapping was indicated by a visual response to a probe flashed in the future receptive field just before the saccade began. We found that many FEF neurons projecting to the SC exhibited predictive remapping. Moreover, the remapping was as fast and strong as any previously reported for FEF or SC. It is clear, therefore, that remapped visual signals are sent from FEF to SC, providing direct evidence that the FEF is one source of the SC's remapped visual signals. Because remapping requires information about an imminent saccade, we hypothesize that remapping in FEF depends on corollary discharge signals such as those ascending from the SC through MD thalamus (Sommer and Wurtz 2002).