Edgar A. DeYoe - US grants

The variety and complexity of visual perception in humans and other primates directly reflects the activity of a diverse system of separate cortical visual areas and their constituent functional subdivisions. The extent and significance of this latter subdivisional structure is only beginning to be appreciated. Nevertheless, it is increasingly apparent that to understand the functional organization of visual cortex as a whole, it will be essential to understand the functional organization of the constituent subdivisions and to understand their organization as multiple, concurrent processing streams. Recent evidence suggests that a key extrastriate visual area, V4, may contain a mosaic of subdivisions the receive their primary visual input from the cytochrome oxidase "thin-stripe" and "inter-stripe" subdivisions of area V2. Consequently, V4 subdivisions may form an essential component of two concurrent processing streams extending from primary visual cortex (V1) to visual areas of the temporal lobe. To provide direct evidence for these subdivisions and to describe their organization, two closely interrelated approaches will be employed. In the first of these, anatomical tracers will be used to reveal the selective connectivity of afferent terminals and efferent projection cells within V4. Particular emphasis will be placed on the relationships of these connections to the subdivisions of V2, to area MT and to the pulvinar. Both "feedforward" and "feedback" components will be examined, and the intrinsic connections of V4 will also be analyzed. The second approach will be to record and map the distribution of simple physiological properties within V4 and then to correlate those properties with the anatomical connectivity. Initially, the emphasis will be placed on responses likely to be associated with the segregated inputs from V2 subdivisions. Later, more complex responses associated with form processing will be studied in order to differentiate the subdivisions more fully and to lay the groundwork for future behavioral experiments. Together, these approaches will provide an integrated view of V4 subdivisions and will chart their relationships with other areas. this information should significantly extend our understanding of the visual processing streams which supply information to the temporal lobe for visual recognition and memory. These experiments are, therefore, an important step toward our ultimate goal of discovering the natural "design" principles and specific mechanisms responsible for our visual abilities. In turn, this work may benefit the treatment of cerebral trauma and pathology, and may contribute to the design of a visual prosthesis for the blind.

The variety and complexity of visual perception in humans and other primates directly reflects the activity of a diverse system of separate cortical visual areas and their constituent functional subdivisions. The extent and significance of this latter subdivisional structure is only beginning to be appreciated. Nevertheless, it is increasingly apparent that to understand the functional organization of visual cortex as a whole, it will be essential to understand the functional organization of the constituent subdivisions and to understand their organization as multiple, concurrent processing streams. Recent evidence suggests that a key extrastriate visual area, V4, may contain a mosaic of subdivisions the receive their primary visual input from the cytochrome oxidase "thin-stripe" and "inter-stripe" subdivisions of area V2. Consequently, V4 subdivisions may form an essential component of two concurrent processing streams extending from primary visual cortex (V1) to visual areas of the temporal lobe. To provide direct evidence for these subdivisions and to describe their organization, two closely interrelated approaches will be employed. In the first of these, anatomical tracers will be used to reveal the selective connectivity of afferent terminals and efferent projection cells within V4. Particular emphasis will be placed on the relationships of these connections to the subdivisions of V2, to area MT and to the pulvinar. Both "feedforward" and "feedback" components will be examined, and the intrinsic connections of V4 will also be analyzed. The second approach will be to record and map the distribution of simple physiological properties within V4 and then to correlate those properties with the anatomical connectivity. Initially, the emphasis will be placed on responses likely to be associated with the segregated inputs from V2 subdivisions. Later, more complex responses associated with form processing will be studied in order to differentiate the subdivisions more fully and to lay the groundwork for future behavioral experiments. Together, these approaches will provide an integrated view of V4 subdivisions and will chart their relationships with other areas. this information should significantly extend our understanding of the visual processing streams which supply information to the temporal lobe for visual recognition and memory. These experiments are, therefore, an important step toward our ultimate goal of discovering the natural "design" principles and specific mechanisms responsible for our visual abilities. In turn, this work may benefit the treatment of cerebral trauma and pathology, and may contribute to the design of a visual prosthesis for the blind.

DESCRIPTION: The long range goal of this project is to develop and use the technology of functional magnetic resonance imaging (FMRI) to elucidate the brain mechanisms responsible for normal vision and for brain-related visual pathologies. to this end, there are several specific aims. A compute model of the functional topography of human visual cortex will be developed and combined with a surface model of cerebral cortex anatomy taken from a widely accepted human brain atlas. Together with improved measurements of human retinotopic organization, the model will be used to test the hypothesis that retinotopic organization and visual area topography are functionally equivalent in humans and monkeys. FMRI will also be used to observe brain activity as subjects perform a vision task designed to identify visual areas associated with sequential stages of visual shape processing. These experiments will be combined with tests of color vision to differentiate areas in ventral occipital and temporal cortex on the basis of their functions as well as their retinotopic organization. Another way that human visual areas can differ is in the relative influence of task factors such as visual processing load and attention. By using a test in which processing load is manipulated, we will test the hypothesis that traditional visual areas are load sensitive but that other task-related areas are not, thus suggesting an important new basis for functionally differentiating cortical areas. Additional tests will be used to quantitatively asses the role of spatial and featural attention in modulating the responses of difference human visual areas. These tests will establish if both types of attention are equally effective, how they interact, and whether there is a gradient of effect across areas at successively higher stages of processing. Together the tests of topographic organization, functional selectivity and task factor control will provide converging evidence for the functional specialization of visual cortex. This information will then be used to account for specific visual deficits in a select group of patients with visual system pathology. A few such patients will be studied comprehensively to provide a more detailed explanation of their deficits that has previously been possible. The results of these experiments, obtained through direct measurement of human brain activity, will significantly advance our understanding of visual system organization and of brain function in general. The project will further develop and test the capabilities of FMRI as a research and diagnostic tool and in so doing will expand its potential as a powerful new paradigm for exploring the human brain.

The ultimate goal of this project is to identify and characterize the neural mechanisms responsible for our perceptual abilities to attend to, and integrate, information from multiple sensory modalities. To this end, functional MRI will be used to investigate polymodal sensory and attentional interactions in the context of visual and auditory motion processing. For example, how does visual and auditory information about the motion of a passing care come together to yield a common percept? The pathways for visual motion processing in the human have been studied extensively and, recently, the auditory motion pathways have been under investigation. Together, these two separate lines of inquiry provide sufficient information to allow the two systems to be compared within individual subjects and, thereby, to investigate in detail how the two systems interact. The project has four specific aims. The first aim is to document the psychophysics of auditory motion perception, especially in the MRI environment. fMRI will then be used to delineate the cortical pathways involved in auditory motion perception. These pathways will be compared with the pathways activated during visual motion perception. A specific goal will be to identify sites where the two pathways converge to yield polymodal responses. The second aim is to identify interactions between the auditory and visual motion pathways resulting from the simultaneous presence of motion stimuli in each modality. Identifying sites where polymodal stimulation results in either enhancement or suppression compared to the unimodal response will be of particular interest. The third aim is to determine how task factors module the activity in the two motion pathways and in areas of convergence. The goal is to determine how the cortical activation patterns change when the subject must combine visual and auditory motion information in different ways to complete a task. The final aim is to identify the neural systems involved in control and allocation of attention to stimuli in the different modalities. The goal will be to determine if there are common or separate systems for controlling attention in each modality. Together, the results of these experiments will provide a detailed accounting of the brain systems responsible for the integration of auditory and visual motion information. Moreover, the comparison of the two motion systems will reveal more general principles governing the functional organization of all the sensory and attentional systems. These results will contribute directly to our understanding of the physiological basis of perceptual defects and attentional neglect resulting from brain pathology.

DESCRIPTION (Provided by applicant): The long-range goal of this continuing project is to develop and apply the technology of functional magnetic resonance imaging (FMRI) to the study and characterization of neural mechanisms responsible for normal visual perception and attention. The project will concentrate on developing a set of neurophysiological principles that characterize the attention-related control of cortical visual processing in humans. (1,2) In a pair of initial experiments, two fMRI-based measures of cortical activity will be critically evaluated for their ability to accurately reflect the behavioral effects of attention. We will examine the ability of these measures to accurately depict the intensive and topographic properties of attention under three different types of attention-intensive tasks: absolute detection, increment detection and feature conjunction detection. We hypothesize that these measures will reflect the specific attentional demands of the tasks. (3) Next, these measures will be used to observe the "top-down" effects of volitional control of attention, first in isolation, then in conjunction with the bottom-up influences of single and multiple objects in the field of view. A novel method for visualizing the "attentional field" will be introduced. (4) In a fourth set of experiments, this approach will be used to test the hypothesis that attention topography can reflect both spatial and object-related characteristics of the visual display. The latter will be tested with occlusion, color, and stereoscopic cues for object segmentation to determine if the induced attentional topography is cue-invariant. (5) An experiment based on "attentional crowding" will be used to identify the cortical site (or sites) of attentional selection. (6) In a final study, we examine the effects of attending to different spatial reference frames (retinal vs object-oriented) on cortical activity. We hypothesize that occipital visual areas will be unaffected by the subject's reference frame but that portions of parietal and/or frontal cortex will be affected. Together, the results of these studies will significantly advance our understanding of the neurophysiological basis of visuospatial attention and the mechanisms controlling the access of visual information to conscious awareness.

[unreadable] DESCRIPTION (provided by applicant): Ten years ago, the field of functional neuroimaging began a period of unprecedented growth spurred by the development of functional magnetic resonance imaging (fMRI) in concert with previously developed imaging techniques and expertise. Since that time, the number of institutions involved in neuroimaging has grown apace and that expansion continues today as increasingly sophisticated applications develop in basic science and, more recently, in clinical practice. Despite this exceptional growth, there has been a shortage of researchers who are well trained in the technology, application and neuroscience of functional imaging. The proposed training program in functional neuroimaging is designed to address this shortage by offering a multidisciplinary program of intensive instruction with an emphasis on the theory and practice of neuroimaging, the physiological basis of imaging signals and neural function, the design and implementation of neuroimaging studies, the subsequent analysis, display and interpretation of neuroimaging data and the application of these techniques to fundamental problems of basic and clinical neuroscience. Applicants to the program are anticipated to have scientific interests ranging from strongly MR biophysics to purely neuroscience. The training program is also designed to meet the needs of trainees at two different levels of career development. For predoctoral trainees, the program seeks to instill a broad understanding of the fundamental principles and practice of neuroimaging and to teach the application of those principles to imaging-related research. In contrast, the program for post-doctoral trainees assumes that the student already has attained expertise in research within a field that the trainee wishes to combine with neuroimaging. The goal in the latter case, is to provide the trainee with the necessary neuroimaging tools and expertise to initiate a unique, long-term program of research incorporating a strong neuroimaging component. The training of students will be undertaken by a unique multidisciplinary team of faculty mentors representing research interests ranging from MR biophysics to cognitive neuroscience and clinical practice. Through an integrated curriculum of didactic course work, research projects, seminars, national and international presentations as well as personal mentoring students will emerge prepared for a career and leadership role in neuroimaging. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The goal of this project is to develop functional magnetic resonance imaging (fMRI) tools for assessing and treating human patients with a brain neoplasm or other focal pathology involving the visual system, especially visual cortex. Such patients can face difficult decisions balancing aggressive, invasive treatment of the pathology with side- effects involving partial or complete loss of vision. The core technology includes methods for creating a brain map of visual cortex function near a cancer site and linking this to a unique display technology, termed a Functional Field Map (FFMap). The latter allows the physician to easily interpret the fMRI activity patterns in terms of vision preservation/impairment and thereby assess the potential side effects of invasive treatment. Using a novel Visual Field Defect simulator, the patient can experience a simulation of potential vision loss that a particular treatment scenario might cause. These tools will aid diagnosis, treatment planning, and follow-up assessment for virtually any localized pathology, but especially cancer. Under this grant (and a subsequent Phase II proposal), the prototype system that currently exists in the Pi's lab will be optimized for clinical use and commercialization. Initial validation tests will be extended to verify the feasibility of commercialization. Proof of concept will be demonstrated by installing a test system in the Radiology Dept. of an affiliated hospital and using it to acquire, analyze and display data from patient volunteers having brain-based vision deficits. A team of experienced physicians including radiologists, neurosurgeons and radiation oncologists will assess the utility of the approach. Successful project completion will produce an installed and functioning prototype system with initial assessment of clinical utility. [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): The goal of this project is to develop functional magnetic resonance imaging (fMRI) tools to assist the diagnosis and treatment of human patients with a brain tumor or other operable pathology. The specific focus of this proposal is to produce a practical, clinic-ready suite of MR imaging methods, analyses and display tools to solve the number one impediment to routine use of fMRI for guiding brain surgery and radiation treatment: risk of brain damage due to the treatment itself. Currently, the primary clinical use of fMRI is to identify healthy brain tissue that might be damaged by surgery or radiation treatment and thereby cause an unintended neurological deficit such as partial blindness or paralysis. Neurosurgeons who use fMRI for this purpose have reported that it allows them to be more aggressive in removing the tumor because they don't have to guess where the healthy brain tissue is located. However, the success of using fMRI for this purpose depends on its ability to reliably distinguish between healthy brain tissue and diseased tissue that can be removed without causing a deficit. Herein, lies a critical problem. fMRI signals are not generated by the brain cells themselves but, rather, by localized changes in blood flow and oxygenation that are triggered when the brain cells become active as the patient performs a sensory, motor or cognitive task. The cascade of cellular events that link changes in brain cell activity to changes in blood flow is complex and can be disrupted by a brain tumor or other disease process. Disrupting this cascade causes neurovascular uncoupling (NVU) and results in a localized loss of the fMRI signal even though nearby brain cells are still functional. If NVU is not detected, healthy brain tissue can be mistaken for diseased tissue and inadvertently resected or irradiated. This can result in treatment-induced deficits such as partial loss of vision or limb movement. Fortunately, there are two promising methods that can be used to detect NVU but they have not been fully tested with patients nor have they been developed into tools that are ready for routine clinical use and distribution to the health care community. Consequently, the specific goal of this project is to address this need through a collaborative effort between imaging scientists and physicians at the Medical College of Wisconsin, Johns Hopkins University and Prism Clinical Imaging, Inc. This Phase 1 STTR project will address the feasibility of combining the two most promising methods, testing the combined method with a small number of patients, and developing prototype software for acquisition, analysis and visualization of NVU-related data. Successful completion of this project will lead to a subsequent Phase 2 project that will focus on testing a larger range of patients and pathologies and creating a commercial product ready for release to hospitals and clinics. It is anticipated that the proposed technology will have a significant impact on the use of fMRI for guiding brain surgery and on the acceptance of fMRI as standard of care for this purpose.

DESCRIPTION (provided by applicant): The diagnosis and treatment of patients with brain tumors and other diseases is often critically dependent on functional neuroimaging (e.g. fMRI) to identify healthy brain tissue that must be avoided during invasive surgery or radiation treatment. But, conventional fMRI often fails (up to 30 percent) or cannot be used with patients who are unable to adequately perform the required behavioral tasks. Resting-state, functional connectivity MRI (fcMRI) provides a potential alternative to task-based fMRI for mapping the brain. fcMRI was first developed at the Medical College of Wisconsin by Biswal and colleagues1 who observed that fluctuations in fMRI signals during behavioral rest are temporally correlated within functionally related cortical networks such as the motor system but not between functionally unrelated networks. Practically, this means that approximately 20 functionally distinct brain systems can be mapped simultaneously with a single 5-10 minute sample of fMRI data obtained while the patient does nothing but rest quietly in the MRI scanner. This approach has exceptional practical utility for clinical applications such as brain mapping prior to brain cancer surgery. Compared to more conventional task-based fMRI, fcMRI is faster, simpler, and less behaviorally demanding since it does not depend on accurate task performance. As a result, it can be used with patients who are anesthetized or too young, too old, too debilitated or too uncooperative to perform a challenging behavioral task. In addition, theoretical connectivity concepts provide potential indicators of brain dysfunction related to pathological changes in functional connectivity. Despite its potential clinical utility, fcMRI has not been optimized for clinical use, nor has its validity as an indicator of brain function been adequately characterized, especially in the presence of operable brain pathologies. Although there are significant initiatives to develop connectivity methods for basic research, far less is being done to promote its use for clinical applications. Indeed, at this juncture, clinically optimized tools for the acquisition, analysis and display of fcMRI data are not available. Thus, the overall goal of this multi-institutional project is to develop a suite of software tools for the routine clinical use of fcMRI and to validate their use with patients suffering from brain cancer, and other operable brain diseases. In this Phase I project, we will focus on developing a prototype system, installing it at suitable hospital sites, and testing it with a small sample of patients in order to demonstrae feasibility. This will lead to a more extensive Phase II project in which the system will be refine for eventual commercial release and tested with a wider range of patients to fully characterize the validity of fcMRI for specific clinical applications. It is anticipated that the successful completion of this project will provide a widely available, professional product, help remove current impediments to use of fcMRI clinically, promote its acceptance within the health care and insurance industries, and extend the benefits of advanced neuroimaging to the treatment of a much wider population of patients with brain disease.

DESCRIPTION (provided by applicant): Even though the fovea occupies only 0.02% of the total area of the retina, 40% of primary visual cortex is devoted to processing visual signals that arise there. Thus, it is not surprising that diseases affecting the structure or function of the foea are especially devastating to visually guided behaviors. Yet fundamental gaps remain in our concepts of how the fovea develops, how foveal structure is disrupted during aging and disease, and how the fovea interacts with more central visual system structures to determine key features of visual function. The overall goal of this proposal is to address these issues using a novel combination of noninvasive imaging technologies including functional magnetic resonance imaging (fMRI), optical coherence tomography (OCT) and adaptive optics scanning light ophthalmoscopy (AOSLO). Albinism is an inherited disorder characterized by absent or reduced melanin pigment in the eye, and often in the skin and hair, with all types manifesting the visual features of foveal hypoplasia, macular translucency, photosensitivity, refractive errors, nystagmus, impaired stereopsis, altered retinostriate decussation, and reduced visual acuity. These specific retinal and cortical features of albinism make it a perfect experiment of nature to examine the knowledge gaps listed above. We propose to do this through the following specific aims: 1) Define the spectrum of foveal morphology in albinism and assess the relationship between pit morphology and retinal melanin, 2) Identify retinal factors contributing t visual deficits in albinism, and 3) Determine the cortical correlates of visual deficits in albinis. The results of this project will provide a more comprehensive understanding of the interrelationships linking melanin, retinal morphology, and cortical organization. This will offer insight into the basis for vision deficits in albinism, which may alter current phenotype/genotype classifications. This work is expected to have a significant positive impact by providing a new framework for understanding and targeting clinical therapies to alleviate the behavioral manifestations of albinism, and by producing sensitive tools for assessing therapeutic outcomes. This proposal directly addresses emerging needs outlined in the National Eye Institute's August 2012 Publication, Vision Research: Needs, Gaps, & Opportunities, and incorporates specific program objectives of the NEI Retinal Diseases Panel: (1) Characterize the macula and perifoveal regions of the retina to better understand the predilection of the macula for disease. (2) Improve understanding of the roles of neuronal activity and molecular events in the formation of central visual circuits during development. (3) Continue to develop and apply noninvasive technologies such as fMRI, OCT, adaptive optics, and confocal imaging to better understand retinal function and changes in disease states.