Anthony M. Norcia - US grants

We propose a program of research designed to elucidate the normal and abnormal development of the visual mechanisms subserving form and motion vision in humans. We will make an extensive series of measurements regarding the development of cortical selectivity for size, orientation and motion. We will determine how the emergence of selectivity for these attributes correlates with improvements in form and motion acuity. Selectivity for orientation and spatial frequency will be assessed using masking paradigms adapted for use with the VEP. Spatial selectivity will also be studied using a newly developed VEP version of the Westheimer sensitization paradigm. We will study the development of temporal contrast sensitivity and will use temporal masking to study the development of sustained and transient temporal channels believed to underly the temporal CSF. We will study the development of the contrast discrimination function which is of central importance in relating threshold visual performance to suprathreshold performance. The development of motion mechanisms in normal and strabismic infants will be studied using a combination of VEP measurements and correlative eye-movement recordings. We will test the hypothesis that visual motion processing may be abnormal in infantile esotropia and the corollary hypothesis that immaturity in cortical motion processing may underlie the transient asymmetries observed in monocular OKN responses. We will determine the clinical utility of VEP vernier acuity and motion acuity measures in the assessment of visual function of infants with strabismus and/or amblyopia.

We propose a program of research designed to elucidate the normal and abnormal development of the visual mechanisms subserving form and motion vision in humans. We will make an extensive series of measurements regarding the development of cortical selectivity for size, orientation and motion. We will determine how the emergence of selectivity for these attributes correlates with improvements in form and motion acuity. Selectivity for orientation and spatial frequency will be assessed using masking paradigms adapted for use with the VEP. Spatial selectivity will also be studied using a newly developed VEP version of the Westheimer sensitization paradigm. We will study the development of temporal contrast sensitivity and will use temporal masking to study the development of sustained and transient temporal channels believed to underly the temporal CSF. We will study the development of the contrast discrimination function which is of central importance in relating threshold visual performance to suprathreshold performance. The development of motion mechanisms in normal and strabismic infants will be studied using a combination of VEP measurements and correlative eye-movement recordings. We will test the hypothesis that visual motion processing may be abnormal in infantile esotropia and the corollary hypothesis that immaturity in cortical motion processing may underlie the transient asymmetries observed in monocular OKN responses. We will determine the clinical utility of VEP vernier acuity and motion acuity measures in the assessment of visual function of infants with strabismus and/or amblyopia.

biomedical equipment purchase;

DESCRIPTION (provided by applicant): Locomotion through the environment and interactions with objects depend on fundamental processes of surface segmentation. This project will study the neural mechanisms that support surface segmentation using a combination of functional Magnetic Resonance (fMRI), electro- electroencephalographic (EEG) and magneto-encephalographic (MEG) imaging studies. Elementary encephalographic aspects of surface segmentation will be studied with reduced cue stimuli that control the availability of temporal frequency, orientation, phase and direction cues as inputs to the figure/ground segmentation process. Cortical areas involved in form and motion-based segmentation will be localized functionally using both fMRI and electromagnetic source estimation techniques. The spatial relationship of this functional activation to visual areas defined by retinotopic mapping will also be determined. These studies will determine how the different segmentation cues are combined in different cortical areas and at different times after stimulus onset. A further goal of the imaging experiments is to determine whether border information is extracted prior to surface information or vice versa. To better understand the neural computations involved in segmentation we will apply a non-linear analysis technique based on binary m-sequences to study the time-evolution of segmentation-related activity recorded from the EEG and MEG. The technique measures time evolution of the strength and sign of interaction (facilitation or suppression) between figure and background as a function of their spatio- spatiotemporal configuration. The technique also yields a functional model of the evoked response that can temporal predict responses to the simpler stimuli that will be used in the imaging experiments. The validity of the model will be tested by comparing model predictions for simple stimuli to those actually measured. Finally, we will examine segmentation performance in strabismus patients with a history of abnormal visual experience during early development that leads to defective or absent stereopsis and nasalward/temporal biases in motion processing. Results from the current project period suggest that these patients will have deficits on figure/ground segmentation that are independent of acuity deficits. This study will also determine whether nasalward/temporal biases previously reported for large field uniform stimuli propagate to the figure/ground segmentation process.

DESCRIPTION (Adapted from applicant's abstract): When very different images are presented to the two eyes, they are not seen simultaneously, rather they alternate in perceptual dominance, a phenomenon known as rivalry. Rivalry is often considered to be the result of competitive interactions between separate monocular representations located at an early stage of visual processing. This view has been challenged recently by new neurophysiological data indicating that modulation of cell responses by rivalrous stimuli occurs exclusively in binocular cells - particularly those outside of early visual areas. New psychophysical demonstrations and rediscovery of several old ones are also incompatible with older views and suggest that rivalry is a higher-order process occurring after the site of binocular convergence. We have developed an objective electrophysiological measure of rivalry that correlates well with subjective reports of rivalry in adults. The technique differs from previous ones in that rivalry can be detected solely on the basis of brain electrical activity. We have applied this technique in normally developing infants between 5 and 15 months of age and have failed to find any evidence of rivalry alternation. Control experiments with non-rivalrous stimuli indicate that the infants have binocular interactions under the spatio-temporal conditions used to test rivalry. The purpose of this project is to examine this apparent disassociation within a developmental context using a new electrophysiological approach. If rivalry and elementary binocular interactions have distinctly different developmental sequences, as suggested by preliminary data, support will be give to the new view of rivalry as a higher-order perceptual phenomenon. If on the other hand, tight linkage is seen between the development of binocular mechanisms and rivalry, support will be given to the traditional view. The proposed experiments are agnostic regarding the new or traditional views and are designed to be useful, regardless of their outcome. Moreover, a substantial amount of otherwise interesting data on orientation-domain interactions and binocularity will also be obtained that will be helpful for understanding the normal developmental sequences of both binocular vision and form vision, independent of their relationship to the development of rivalry.

DESCRIPTION (provided by applicant): Vision in complex environments requires the ability to integrate local measurements of orientation and motion over large parts of the visual field. Moreover, this integration must be selective for stimuli that are behaviorally relevant and the visual system must be able to separate relevant stimulus information from background clutter. How this is accomplished will be studied during normal visual development and in patients with amblyopia using a combination of psychophysical, electrophysiological and functional imaging approaches. We will link the cortical sources determined by fMRI to neuronal activity recorded with high-density EEG/MEG using source localization techniques. The degree to which attention influences response sensitivity will be determined by comparing EEG responses when observers are making motion/form relevant discriminations on the test stimuli versus responses made when the observers are performing an attentionally demanding distractor task. Sensitivity to global motion and form stimuli will be determined in visually mature observers with a history of strabismus and/or amblyopia using both psychophysical and electrophysiological measures. Developmental sequences for the same stimuli will also be determined in normally developing infants and children. These tasks are likely to probe activity in extra-striate areas which may be particularly vulnerable due to extended developmental sequences.

DESCRIPTION (provided by applicant): Support is requested for four additional fellows in the longstanding fellowship training program at the Smith-Kettlewell Eye Research Institute. Although the program has been successful in training dozens of research fellows in visual processing and scores of clinical ophthalmology fellows over the past three decades, it falls far short of the needs of the current faculty of eighteen investigators. The current program funding can support postdoctoral fellows to work with only about a quarter of the investigators. The need for fellows is particularly critical at Smith-Kettlewell, an independent institute devoted purely to research, for two reasons: 1) they bring fresh ideas and energy to established laboratories during their training and 2) they learn to conduct projects independently with minor oversight from their mentors. Conversely, the established investigators are in an excellent position to offer high quality training to fellows because they are fulltime researchers without teaching responsibilities in the traditional university setting. The goal of the application is therefore to approximately double the scale of the fellowship training program at Smith-Kettlewell. The areas of expertise are spatial vision, infant vision (normal and abnormal), subcortical processing retinal processing and its disorders, strabismus and amblyopia, eye movement control, eye muscle physiology, visual rehabilitation, computational neuroscience, sensory impairment, stereopsis, motion, cortical processing, and computer vision. Smith-Kettlewell investigators make a substantial contribution to the national research effort in ophthalmology and visual disorders, with most of the faculty serving on NIH, NSF or NIDDR scientific review panels, all faculty qualifying to receive federal funding for their research, and many members serving on editorial boards and as officers of professional organizations who have oversight for programming meetings in the discipline. The current fellowship program is already fully coordinated with the NEI requirements for INRSA postdoctoral programs, including a didactic component, ethics training and stipend levels. Integration of the INRSA component of the program with the current other support will therefore require no further adjustments. The INRSA component will fund exclusively fellows with U.S. residency certification while the other institutional components will fund both the remaining U.S. and non-U.S. fellows on an equal basis.

DESCRIPTION (provided by applicant): The fundamental goal of perception is to infer the structure of the world through an interpretation of temporal and spatial regularities in sensory stimulation that map onto structures in the environment such as objects and surfaces. The goal of this proposal is to trace the emergence of low-level object processing operations as they evolve in time and cortical area and to study how rapid, on-line learning or adaptation modifies these responses. We propose to study the mechanisms by which the visual system segments the visual scene into objects and surfaces and how it adapts its responses to stimuli with varying levels of temporal regularity using a combination of EEG source-imaging and functional MRI techniques in normal adults. In the first Aim we will study how attention interacts with low-level mechanisms involved in figure-ground segmentation. A novel, multi-input stimulation and analysis method will be used to separate response to figures and their backgrounds. In the second Aim, we will determine how temporal predictability shapes the accuracy behavioral shape discrimination by correlating behavioral performance with activity in visual and control areas that occurs before the presentation of predictable targets. A second goal is to determine if anticipatory evoked activity made in response to temporally regular stimuli can occur implicitly. The third Aim will record responses to predictable and unpredictable stimuli of varying degrees of salience. Anticipatory activity will be isolated by subtracting reconstructions of the evoked response derived from random stimuli from those measured with temporally regular stimuli over a range of stimulus salience. These data will be used to test the hypothesis that anticipatory activity is generated in prefrontal cortex and produces its largest effects in target areas of occipital/occipital temporal cortex for low salience stimuli. PUBLIC HEALTH RELEVANCE The tasks we will study require integrated activity throughout the visual hierarchy, in executive control areas of pre-frontal cortex and in areas responsible for sensory motor integration and motor response. The methods we develop to link brain activity and behavior at each of these levels will be relevant to understanding and managing disorders of visual processing, visual memory, visuo-motor integration and motor execution. Because the methods are non-invasive they can be applied directly to clinical populations in future studies of Cortical Visual Impairment, traumatic brain injury, stroke, dementia and congenital brain malformations. These disorders frequently compromise visual processing and each often involves significant compromise of motor and cognitive functions. Careful adaptation of the protocols that will be developed in this proposal may provide information relevant to the diagnosis and management of these disorders.

The fact that we view the world through two eyes provides us with the computational basis for exquisite sensitivity to the structure and layout of the three-dimensional world. This sensitivity is derived, in large part, through a combination of retinal disparity and motion cues. Our understanding of the computations and cortical mechanisms that underlie mature depth perception is still rudimentary and there is a lack of neural developmental data regarding sensitivity to depth cues outside of the earliest visual areas and youngest ages. In the first Aim, dynamic random dot stereograms will be used to measure the complete developmental sequence for a critical performance limit of the stereoscopic visual system ? the minimal disparity that can be detected (stereoacuity). These limits will be measured in developing infants, children and adults using Steady-state Visual Evoked Potentials and will be related to measurements of spatial contrast sensitivity in the same participants. The comparison will allow us to determine whether low-level stimulus visibility is the critical limiting factor in the development of stereopsis or whether more central limits are involved. In the second Aim, sensitivity to binocular motion cues will be studied across development, as these cues provide independent information for scene layout and may involve mechanisms different from those responsible for coding binocular disparity. Preliminary data suggest that a binocular motion mechanism sensitive to differences in velocity between the two eyes that is present in the adult is absent in infants. This Aim will provide the complete developmental sequence for this system and will determine its relationship to monocular motion sensitivity. The third Aim will use functional Magnetic Resonance Imaging (fMRI) to localize disparity and binocular-motion-related activity within identified visual areas of the healthy adult visual system. These data will provide evidence regarding opponent binocular mechanisms we hypothesize form the foundation of figure-ground segmentation/depth estimation and that are selectively immature in infancy. The fMRI data will also identify areas most likely to support the perception of depth from disparity and binocular motion cues. The data sets we will provide will be the first functional measurements of the development of sensitivity to disparity, motion and contrast made using a consistent and sensitive methodology throughout the development of key mechanisms of spatial vision. This research addresses fundamental questions about how changes in cortical response organization over human visual development allow the visual system to encode the spatial layout of the environment. The timing of the maturation sequences of these processes is directly relevant to developmental disorders of visual processing ? especially strabismus and amblyopia. Importantly, the methods used here to study normal visual development are readily adaptable for use in clinical research. The large-scale EEG, fMRI and structural MRI data sets that will be generated by the project will be documented and deposited for others to use for testing models of visual development and for refining new multi-modal imaging approaches.

DESCRIPTION (provided by applicant): The processing of binocular sensory cues for scene layout and observer motion is inextricably intertwined with motor control of the pointing direction of the eyes. It is of great importance to understand the neural mechanisms underlying this relationship in order to understand developmental failures that can lead to strabismus and the loss of functional binocularity. The normal developmental sequence for sensory binocularity is poorly understood and it has only recently been appreciated that 3D-specific motion signals also contribute to depth perception. It is shown here for the first time, that these 3D motion cues provide an important input to vergence eye movements. The normal developmental sequence for sensitivity to these motion cues is currently unknown. Neither is it known how these signals interact with disparity cues to control eye movements or how they are affected in strabismus. Therefore, each Aim of the proposal is organized around the inter-relationship between, and parallel processing of, horizontal disparity and 3D motion cues. The first Aim will use high-density EEG recordings to determine the developmental sequences for disparity and motion processing systems in normally developing infants and children. The working hypotheses that sensitivity to relative motion and disparity both depend on the development of domain-specific spatial interactions, that these interactions develop earlier in the motion system than they do in the disparity system and that motion-cues augment stereo cues for motion-in-depth early in development will be tested. The second Aim will combine fMRI and high-density EEG recordings in normal adults to determine the timing and pattern of spatial interactions that underlie the processing of relative motion and disparity cues across identified visual areas. The hypotheses that relative motion stimuli more effectively activate lower-level visual areas than do relative disparity stimuli and that manifestations of domain-specific surround organization will be more apparent in early retinotopic cortex for relative motion stimuli will be tested. The third Aim will follow up on pilot data indicating that 3D motion cues provide an independent and largely involuntary velocity input to vergence eye movements. The fourth Aim will test the hypothesis that developmental asymmetries of motion processing that are common in early onset strabismus are related to a more general developmental failure of 3D motion processing mechanisms. The proposed studies will provide a detailed understanding of both normal and abnormal binocular vision and its development, both by testing of novel hypotheses about sensory processing and motor control, but also through the use of powerful new approaches to EEG recording that will be readily transferable to studies of the effects of treatment for binocula vision and other disorders of visual processing during the developmental critical period.

? DESCRIPTION (provided by applicant): Neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), are characterized by abnormalities in baseline cortical excitability that are believed to be caused by an abnormal, system-wide balance between excitation and inhibition. Mounting evidence has linked baseline cortical excitability to abnormalities in the sensory systems. as manifested by both over- and hypo- reactivity to sensory stimuli and by the high prevalence of epileptiform EEG activity in the majority of neurodevelopmental disorders including ASD and ADHD. Sensory systems rely on a set of well-characterized network of mechanisms whose functioning directly depends on a precise balancing of excitation and inhibition. The aim of this investigation is to use sensory evoked responses as a means to quantitatively assess baseline cortical excitability in two common neurodevelopmental disorders, ASD and ADHD. These measurements will be made via Steady-State Visual and Auditory Evoked Potentials. Patterns sensory responses measured electrophysiologically will be compared to patterns of behavioral hyper/hyposensitivity measured via a well- characterized parental questionnaire and examiner-administered performance evaluations. These measurements will be obtained from 40 children with ASD, 40 children with ADHD and 40 matched controls. The immediate goal of the project is to determine whether specific patterns of sensory evoked potentials are associated with behavioral indices of disturbed sensory processing. The long-term goal of this proposal is to develop sensitive and objective measures of cortical excitability for use in classifying neurodevelopmental disorders. An ability to detect and quantify underlying alterations in cortical excitability in infancy and ealy childhood would be of significant value in the diagnosis, classification and treatment management of common neurodevelopmental disorders. The present proposal is a fundamental step toward the achievement of this purpose and this approach is consistent with the NIMH Strategic Plan for the development of new ways of classifying psychopathology based on dimensions of observable behavior and neurobiological measures.

Non-invasive brain stimulation approaches such as transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (TES) can be used for two purposes, each with wide application in fundamental visual neuroscience and in visual rehabilitation. In the first of these, stimulation is used to manipulate activity in cortical networks with the goal understanding the causal role of the targeted network in generating brain responses and in perception/behavior. In the second, stimulation is used in a neuromodulatory role to induce plastic remodeling of cortical networks, either on a short-term or long-term basis. The focus of this proposal is the development of new experimental systems for combining visual and electrical stimulation that will achieve these goals. The central hypothesis of this research is that Transcranial Alternating Current Stimulation (TACS), a variant of TES, acts via constructive or destructive summation of the TACS field with the intracellular membrane potential of polarizable neurons. This hypothesis and the related hypothesis that short-term persistent effects of TACS will be proportional to the effects measured online will be tested using a combination of Functional Magnetic Resonance Imaging (FMRI), Steady-State Visual Evoked Potentials (SSVEPs) and perceptual reports. The rationale for the central hypothesis is based on several observations: first, periodic visual stimulation generates visual responses (SSVEPs) that are directly and precisely related to the stimulus frequency. Second, because TACS is also periodic and extremely narrowband, it should be possible to directly target the periodic visual response itself via summation of synaptic and electrical potentials within task-active neurons. Finally, because prior work has suggested that externally applied electric fields primarily modulate elongated neurons, the effects of TACs are predicted to depend on both the orientation of the cortical tissue and the direction of the applied TACS field. This central hypothesis will be tested in Aim 1 by determining whether BOLD responses to visual contrast depend on the relative phase of TACS and visual stimulation and the relative orientations of the cortical surface and the applied field. Aim 2 will test the hypothesis using the SSVEP and perceptual reports during binocular rivalry and binocular slant discrimination tasks. Aim 1 will also use FMRI to determine if TACS effects persist after the stimulation is turned off and if so, whether the TACS effect depends on the relative phase of visual and electrical stimulation as would be expected if the central hypothesis is correct. The experiments of this proposal will determine whether two of the main hypothesized mechanisms for TACS effectiveness derived from animal experimental models can be identified and brought under experimental control in human. They will also determine if TACS results in a short- term persistent effect on visual responsiveness. The new experimental approaches developed in this proposal have the potential for wide application in visual neuroscience and ophthalmology via their possible ability to exert causal control over neural activity and to elicit plastic changes in complex visual networks.

This project will use a combination of structural and functional measurements to test the hypothesis that early- stage damage in human glaucoma occurs first in the inner plexiform layer (IPL) of the retina ? especially its OFF sub-lamina ? as suggested by murine glaucoma models. In the first Aim, we will use a novel visible-light optical coherence tomograph (VIS OCT) to study structural changes in the retina of glaucoma patients. The newly developed VIS OCT has sufficient image contrast and resolution to segment the IPL boundaries and to define sub-lamination in volumetric OCT data, something not currently possible with existing near-infrared OCT instruments. We will make comparative measurements within the IPL and between the IPL, the ganglion cell layer (GCL) and the retinal nerve fiber layer (RNFL). Because data from mouse models of glaucoma suggests that early damage occurs preferentially within the OFF sub-lamina of the IPL, we will make separate VIS OCT measurements biased for the OFF- and ON-sublaminae of the IPL and use machine learning approaches to determine whether a similar damage process can be demonstrated in human. To test whether OFF-pathway function is preferentially lost in glaucoma, we will use a novel Steady-State Visual Evoked Potential (SSVEP) paradigm that employs sawtooth increments and decrements to bias the measurement to ON vs OFF pathways, respectively, a paradigm our data suggests discriminates glaucoma from control patients. The second Aim will optimize this SSVEP measurement for testing localized areas of the visual field. The third Aim will make comparative measurements of visual-field, VIS OCT and SSVEP loss patterns in a large sample of glaucoma patients and in age- and sex-matched controls. Thickness and interface reflectivity amplitude maps derived from VIS OCT imaging of the RNFL, GCL and IPL including sublaminae will be correlated topographically with visual field defects to assess the relative sensitivity of our structural biomarkers at and near visual field locations with demonstrable losses on conventional (Humphrey) perimetry. Similarly, SSVEP responses from different locations in the visual field will be correlated topographically with visual field loss patterns and to VIS OCT losses, with special emphasis on correlating structural damage in OFF vs ON sub-laminae of the IPL with the functional correlates derived from regional decremental and incremental SSVEPs. Separately and in combination, our structural and functional measurements are designed to provide strong tests of the biological hypothesis that the OFF pathway is preferentially damaged in human glaucoma, and to reveal new biomarkers for the disease.