Anna W. Roe - US grants

The mammalian cerebral cortex is characterized by multiple cortical areas, each with a separate representation of the sensory world. However, the role of multiple representation in sensory information processing is unknown. As a prelude to understanding how multiple cortical areas cooperatively process visual percepts, this proposal aims to study contour representation within V2 (the second visual cortical area) and its interaction with contour representation in V1 (primary visual cortex). Orientation selective cells in V1 are well known to be responsive to luminance contrast edges. However, many visual contours are not defined by luminance contrast but rather by higher order features (such as occluded contours or texture pattern borders). Area V2, the second major stage of visual cortical processing, is characterized by cells which prefer such higher order features. This proposal will explore the idea that different cortical areas process different levels or abstractions of visual contours and examine how these separate representations interact. Specifically, the organization and interactions between cells responsive to real contours and those responsive to higher order contours will be examined. These circuitries will be examined for each of the color, form, and disparity domains which together comprise V2. The stated goals will be achieved by using a combination of optical imaging, electrophysiological, and anatomical methods. V1-V2 interactions will be studied with both cross correlation methods and optical imaging of V1-V2 activation in response to "spot" stimuli (a functional tract tracing method); these will be compared with connectivity patterns revealed anatomically. In addition, differences in contour saliency due to geometrical or featural characteristics will he related to stimulus- related changes in interaction patterns. By elucidating the neural circuitry underlying contour perception in V1 and V2, this research will offer insight into whether different cortical areas mutually reinforce the same information (i.e. interactions between similarly oriented real and higher order contour cells) or whether a more hierarchical relationship exists in which the outputs of one area are used to construct a quite different representation in another area (interactions between differently oriented real and higher order contour cells). Alternatively, different strategies could be used under different contexts, a possibility that would be supported by stimulus-related changes in connectivity or activation of different populations of contour cells in V2.

DESCRIPTION (Provided by applicant): The goal of this research proposal is to understand the role of primary visual cortex (V1) and second visual cortical area (V2) in real and illusory brightness perception. In the previous support cycle, we investigated the organization of real and illusory contour processing domains in V1 and V2 of the macaque monkey visual cortex. We found that signals from V1 and V2 are similar during the processing of real contours, but complementary during that of illusory contours (Ramsden et al., 2001). These findings may suggest that the encoding of contour identity is dependent on the coordinated activation of multiple cortical areas. In this support cycle, we propose to examine whether the processing of real and illusory brightness bears any parallels with that of real and illusory contour processing. Our perception of surface brightness is determined both by absolute luminance as well as by luminance contrast. Recently, studies using simultaneous contrast stimuli established that a brightness response to luminance modulation of flanking regions can be observed in Area 17 of the cat (Rossi et. al., 1996; Rossi & Paradiso, 1999). Although this demonstrated that brightness percepts due to surface luminance contrast can be implemented as early as primary visual cortex, it remained unclear whether contrast borders also contribute to this brightness response. Here, we propose to examine the neural processing of a border-induced brightness percept, the Craik-O'Brien-Cornsweet illusion. Using electrophysiological and optical imaging methods, we aim to examine the responses of V1 and V2 in both the cat and monkey to real and border-induced brightness stimuli. We aim to localize cortical compartments in V1 and V2 involved in real and illusory brightness processing. In addition, we will determine, by studying single-unit responses, the phase relationships of real and illusory responses, and the spatial extent of illusory response in the cortex. By using different illusory brightness conditions, we aim to identify surface and border contributions to the neural encoding of brightness perception.

DESCRIPTION (provided by applicant): This proposal aims to study the stability of cortical representation by examining cortical maps under different states of anesthesia and alertness (pentothal and isofluane anesthesia, and awake state). Previous studies have hypothesized that different parts of single thalamocortical arbors have different degrees of dominance in Area 3b and that the effects of these secondary arbor inputs may be masked under some conditions and revealed under others. Using optical imaging and electrophysiological methods, we will probe this hypothesis by examining three aspects of finger pad representation in Area 3b and Area 1 of the squirrel monkey: topography, vibrotactile information (pressure SA, flutter RA, and vibration PC), and spatial integration (two digit). We will examine whether digit representation can, in contrast to the standard somatotopic maps, take on non-topographic organizations that are characterized by hotspots and secondary activation zones. We will examine whether SA, RA, and PC inputs can map in both overlapping and segregated manners in the superficial layers. To examine spatial integration in Area 3b and 1, we will examine whether mapping with simultaneous two-finger stimulation paradigm will result in an apparent shift in topography, and whether such a shift is more pronounced in Area 1 and more pronounced in the awake state. These examinations of alternative and shifting topographies are likely to modify the definition of topographic organization in SI and what shifting topographies are likely to modify the definition of topographic organization in SI and what topographic organization is used for in the awake animal. Furthermore, these studies may reveal that the establishment of topography is area-specific and is based on a stimulus-driven or behavior-driven integration of features rather than a simple representation of the sensory epithelium.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The goal of this research proposal is to develop a fast temporal resolution optical imaging methodology for use in awake, behaving monkeys. If successful, this methodology would provide online visualization of brain function at both high spatial (10's of ums) and high temporal (1-10 msec) resolution. Intense effort has been devoted to studying anatomical organization and physiological responses of sensory cortex in anesthetized and awake monkeys. However, little is known about the spatial patterns of activation in prefrontal cortex of awake, behaving animals during performance of working memory tasks. The goal is to observe clustered and distributed clusters of neuronal activation of cortical activity during behavior. These data would also provide a critical link between single-unit physiology, functional imaging studies, and behavioral studies. Importantly, the proposed technology development will provide new methodologies for studying spatial (functional organizational) and temporal aspects of cortical processing relating to vision, attention, memory, and cognitive function. Clinical relevance of data obtained from this approach would be relevant to cognitive dysfunctions in diseases such as schizophrenia. The specific aims of this proposal are: 1) development of fast optical imaging system for awake, behaving monkeys. This aim would include development of voltage sensitive dye methodology, noise reduction techniques for optical detection of neuronal activity, rapid image processing techniques suitable for large volumes of streamed data, and tandem electrophysiological recordings. 2) application of this method to study working memory processes in prefrontal cortex. Macaque monkeys would be trained on oculomotor delay response tasks. Delay period activity in prefrontal cortex would be imaged at high temporal (1-10 msec) to monitor changing spatiotemporal activity patterns depending on task demands. This methodology will provide a new approach for examining relationship of cortical organization with behavior, one that will complement the spatiotemporal capabilities of other existing technologies such as fMRI and single unit electrophysiology. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The goal of this research proposal is to develop the optical imaging methodology for use in awake, behaving monkeys. Optical imaging has been highly successful in revealing cortical organization in anesthetized animals. We propose to develop this method to study cortical activation patterns in somatosensory physiological responses of somatosensory cortex in anesthetized an awake monkeys. However, little is known about the spatial patterns of activation in awake, behaving animals. The proposed methodology is a highly novel approach to the study of somatosensory cortical function. By directly relating high spatial and temporal resolution images of cortical activation patterns to behavior, it promises to have a high impact on views of cortical function. We have two aims. One aim is to develop an optical imaging system capable of both high spatial and temporal resolution for use in awake, behaving monkeys. Both intrinsic signal and voltage sensitive dye imaging capabilities will be incorporated into a single system. This involves hardware and software development, testing in behaving monkeys, and development of new data analysis methods. Our second aim is to do exploratory optical imaging studies in awake monkeys performing tactile tasks. There are significant differences in topography, function organization, and inter-areal activations between anesthetized an awake SI. We aim to explore whether these differences correlate with factors such as attention and task- dependent context. Given our preliminary data, it is highly likely that these studies will prove fruitful and will form the basis for future R01s in behaving monkeys. The proposed methodology is novel and will permit a new approach to the study of cognitive functions. Further, this type of functional imaging in behaving monkeys will provide a much needed link between bodies of single-unit physiology, fMRI, and behavioral studies. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This research will be done in collaboration with Dr. Laszlo Negyessy at Budapest, Hungary at Semmelweis University as an extension of parent grant NIH R01 NS044375 (PI: Anna W. Roe). The goal of the proposed studies is to investigate the neuroanatomical basis of tactile information processing in SI of the squirrel monkey. The goals of the parent grant are to 1) study the functional organization of vibrotactile modality- specific (pressure, flutter, and vibration) representation in Area 3b and 1, and 2) compare the simple vs. complex response preferences in Area 3b and 1. The studies proposed in this Firca will be guided by and integrated with the optical imaging and neurophysiological studies conducted under the parent grant. Neuroanatomical tracer injections (both anterograde and retrograde) will be made into functionally identified domains in Areas 3b and 1. In Aim 1, we will examine modality-specificity of vibrotactile networks within Areas 3b and Area 1. In Aim 2, we will examine topographic specificity of connections within Areas 3b and 1. In Aim 3, in ultrastructural studies, we will examine synaptic relationships of GABAergic targets of synapses formed by the intrinsic-, and interareal connections to help interpret whether functional effects of specific connections are excitatory or inhibitory. These data will provide an anatomical underpinning to imaged vibrotactile networks, to spatial topographies, to functional comparisons between Areas 3b and 1, and to maps of perceptual phenomena such as the funneling illusion. There are very few studies examining local anatomical circuitries within somatosensory cortex and to our knowledge none have been conducted in an integrated fashion with functional studies of local functional organization and perceptual processes. These anatomical data will be highly valuable in their own right, but will be even more so when interpreted in parallel with functional studies in the parent grant. [unreadable] [unreadable] [unreadable]

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to investigate how the brain encodes tactile motion processing in the brain. Responses within two different stages of somatosensory cortical processing, primary (SI) and second (SII) somatosensory cortex, will be examined. Central to understanding their functional roles is finding out what distinguishes one area from another. By using simple versus complex stimuli, we aim to distinguish between areas whose responses are closely associated with the physical nature of the stimulus and areas whose responses are invariant and more closely reflect the motion percept. We will employ optical imaging, voltage sensitive dye imaging, BOLD fMRI, single unit recording, and anatomical tracing methods to address these questions. These experiments will elucidate the neural circuitries underlying tactile behavior and attention, understanding that will have clinical relevance for, for example, recovery of function from stroke and development of tactile prosthetics.

Description (provided by applicant): The goal of this proposal is to investigate the role of visual area V4 in representation of and attention towards different features in the visual scene, such as contour, color/brightness, and depth, features that ultimately lead to processing and recognition of form. While in other early visual areas such as area V2, these features are represented in distinct organizations. However, due to the complexity of this area, the functional organization of area V4 has been elusive. To provide a better understanding of the functional architecture underlying form recognition and visual attention, we propose to use optical imaging, voltage sensitive dye imaging, single unit recording, and anatomical tracing methods. These experiments will elucidate the neural circuitries underlying visual behavior and attention, understanding that will have clinical relevance for, for example, attention deficit disorder and epilepsy. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to investigate the functional organization of visual area V4 in the primate cerebral cortex. This is an area involved in form perception and visual attention. We will study how the organization of area V4 relates to form perception and attention. Organizations underlying spatial and featural attention will be examined. These studies will elucidate the neural circuitries underlying visual behavior and attention, understanding that will have clinical relevance for conditions such as cortical strokes, attention deficit disorder, and schizophrenia.

DESCRIPTION (provided by applicant): The goal of this proposal is to achieve a method to map circuits in the brain using near infrared laser stimulation in the FMRI scanner. By using the laser to focally target 100-500um sized building blocks of cortical function (cortical functional domains), we can selectively activate networks that are functionally linked to the targeted domains. Such a capability will allow us to map non-invasively, without the introduction of electrodes into the brain, functional circuits in the cerebral cortex of the primate. Both local an global connectivity patterns will be examined with fMRI, optical imaging, and electrophysiological methods. Such capability will give us a circuit diagram of how basic cortical building blocks produce specific brain functions in behavior and, in turn, will lead to development of methodologies relevant for neurological, neuropsychiatric, and neuroprosthetic applications. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to achieve a method to map circuits in the brain using near infrared laser stimulation in the FMRI scanner. Said capability wil allow us to map circuits of small 100-500um sized building blocks (functional domains) in the cerebral cortex of the primate without the introduction of electrodes into the brain, and provide a circuit diagram of how basic cortical building blocks produce specific brain functions. This knowledge will be relevant for human neurological, neuropsychiatric, and neuroprosthetic applications, which in turn, will lead to development of methodologies that target these building blocks.

DESCRIPTION (provided by applicant): Optogenetics refers to a cutting-edge set of molecular methods that allows for light-based control of targeted neurons in intact brains. These methods have immense potential as a basic research tool to determine the role of specific neuronal populations in healthy and abnormal brain function. In addition, further development of these methods may lead to new types of treatments for neurological and psychiatric disorders, as well as a new class of prostheses for those with sensory impairments. This project is aimed at further developing these methods so that they can achieve their basic research and clinical potential. This proposal introduces key improvements in the molecular methods as well as fundamental improvements in their application to the study of higher-order perceptual and cognitive functions. Critically, the approach of this proposal is minimally invasive and hence, unlike previous methods, causes little to no tissue damage. In addition, the improvements introduced by this proposal allow for more precise targeting of neurons and more potent control of the responses of those neurons. This proposal uses these methods to systematically determine their efficacy at both the neuronal and the behavioral levels. A key innovation of this approach is the development of an optogenetic window. This window will permit long-term health of the cortex, functional mapping prior to delivery of molecular agents, precise targeting of molecular agents to specific functional sites, and assessment with established optical imaging, electrophysiological, and behavioral methods. This proposal will allow patterns of neuronal modulation (both inhibitory and excitatory) to be related to specific perceptual and behavioral effects. The successful completion of this project will have enormous benefits for basic research into higher-order perceptual and cognitive functions, and will provide a solid foundation for the development of new treatments for the sensory impaired as well as those with psychiatric or neurological disorders.

? DESCRIPTION (provided by applicant): The goal of this proposal is to investigate the organization and circuitry within the hand and digit region of primary somatosensory cortex in nonhuman primates. Hand and digit behavior are defining aspects of object identification in primate behavior, and are central to different types of tool use, typing, texting, and body language. Despite this, little is known regarding the cortical circuitry underlying different stage of sensory (tactile and proprioceptive) processing. This proposal will use multiple anatomical and functional approaches to discover the intra-areal and inter-areal connectivity patterns between functional columns in the hand representation of primary somatosensory areas (3a, 3b, 1, and 2). These approaches will include anatomical tract tracing and functional tract tracing (using optical imaging and fMRI during focal electrical and pulsed near infrared laser stimulation). The role of these circuits during behavior will be examined. These studies will provide invaluable data for incorporation of sensory guidance in manual motor prosthetics, an area in which there is currently little understanding.

PROJECT SUMMARY Understanding how the brain processes what we see from the very center of our visual gaze (foveal vision) is essential for maintaining healthy vision, including high spatial acuity vision, color vision, and visual attention. Deficits of central vision lead to blindness as in the case of macular degeneration, or loss of depth perception as in the case of lazy eye (amblyopia). Macaque monkeys have visual systems very similar to humans and thus are an ideal animal model for studies of foveal vision. During the first few months of postnatal development in the macaque monkey and first few years of life in the human, retinal photoreceptors undergo an important migration to establish the adult foveal cone and rod distribution. Despite the importance of this part of vision, there is very little known regarding cortical representation of the fovea during development. Here, we investigate the relationship between postnatal retinal photoreceptor migration and changes in foveal cortical representation in infant monkeys. Using a combination of in vivo retinal photoreceptor imaging and cortical optical imaging and electrophysiological approaches, we aim to answer questions regarding the relationship between retinal cone photoreceptor migration and changes in foveal cortical representation in the first few months of postnatal development. Multiple developmental timepoints will be studied over the first 3 postnatal months, a period when foveal cone density can be mapped with adaptive optics. Paired retinal and cortical investigation will be conducted and data correlated. Revelations regarding the mechanisms of cortical plasticity during development will have great impact on understanding the development of central vision, computational models of cortical development, and on understanding retinal and cortical bases of visual developmental disorders which may lead to new approaches to treat neurological diseases like amblyopia and improve capabilities of brain-machine interfaces for the treatment of blindness.