Lotfi Merabet - US grants

DESCRIPTION (provided by applicant): Current evidence suggests that the occipital cortex (normally associated with visual perception) actively participates in non-visual sensory tasks. For example, it has been demonstrated both in sighted and blind individuals that this area is implicated in the processing of sensory information obtained through touch. The purpose of this research proposal is to investigate the neurophysiology and neuroplasticity of cross-modal sensory interactions. Specifically, the study has three aims: (Aim 1). In congenitally blind and sighted individuals, what roles do occipital (visual) cortical areas play in tactile spatial discrimination tasks? (Aim 2) Does the tactile exploration of complex objects and visual scenes (e.g., faces and houses) by sighted and blind individuals activate known higher-order visual areas? (Aim 3) Does tactile stimulation modulate occipital cortex function? We will employ fMRI and TMS to pursue these questions. Subjects will perform spatial discrimination and object recognition tasks to tactile presented stimuli (simple raised dot texture patterns and complex objects such as faces), fMRI will be used to map and compare the cortical areas activated during these tactile tasks in the sighted and blind. In a second set of experiments, we will assess the modulation of occipital cortex activity and function during a cross-modal visuo-tactile task. TMS will be used to induce and assess changes in phosphene perception as a function of simultaneous tactile stimulation. The candidate wishes to learn, master and combine the techniques of fMRI and TMS with the goal of becoming an independent clinician-scientist. The proposed experiments will contribute to our understanding as to how objects are represented within the visual brain and how information obtained from touch contributes to this processing. Furthermore, comparing these processes in the blind will help uncover the adaptive mechanisms underlying object representation in the absence of vision. These results are likely to have implications for both the rehabilitation and education of the blind and visually impaired.

DESCRIPTION (provided by applicant): We propose a combined field and laboratory approach investigating cognitive spatial mapping in the blind through virtual navigation and assessing the transference of acquired spatial knowledge in a real-world navigation task. Training and evaluation of navigation performance will be carried out with a user-centered, computer-based navigation software platform called Auditory-based Environment Simulator (AbES). This software was developed to assist in orientation and mobility (O&M) training by introducing a blind user to an unfamiliar environment through immersive virtual navigation. Using auditory spectral cues, a user learns to build a cognitive spatial map of their physical surroundings. In this study, participants will interact with the software and navigate through a simulated virtual environment that represents an actual physical space. In a first phase of the study, we will compare learning and spatial cognitive map development in early and late blind individuals using the software in two different modes: 1) directed navigation of pre-determined routes guided by a facilitator and 2) self-directed (or "open discovery") navigation under the pretext of an exploration-theme video game. The ability to translate acquired spatial information will then be assessed with navigating tasks carried out in the actual physical environment. In a second phase of the study, we will investigate the neural correlates associated with spatial navigation. Using functional magnetic imaging (fMRI), neural networks associated with navigation will be assessed in sighted compared to early and late blind individuals and as a function of overall behavioral performance over time. Secondly, the functional contribution of identified cortical areas will be assessed by reversible cortical disruption using transcranial magnetic stimulation (TMS). The results of this study will 1) contribute new insights towards our understanding of the neural mechanisms associated with navigation and 2) develop novel approaches for orientation and navigation training in the blind. PUBLIC HEALTH RELEVANCE: We propose to investigate cognitive spatial mapping skills in the blind through virtual navigation of real-world environments using a computer-based software approach. The results of this study will contribute new insights towards our understanding of the neural mechanisms associated with navigation and develop novel approaches for orientation and mobility training in the blind.

DESCRIPTION (provided by applicant): We propose a combined field and laboratory approach investigating large-scale cognitive spatial mapping in the blind through virtual navigation, and assessing the transference of acquired spatial knowledge in real-world indoor and outdoor navigation tasks. Training and evaluation of navigation performance will be carried out with a user-centered, computer-based navigation software platform called Haptic Audio Game Application (HAGA). This software was developed to assist in orientation and mobility (O&M) training by introducing blind users to an unfamiliar environment through immersive, simulation-based virtual navigation. Using iconic and spatialized auditory cues and vibro-tactile feedback, a visually impaired user learns to build a cognitive spatial map of their surrounding environment. Using a self-directed, free exploration strategy, users interact with HAGA to navigate through a simulated indoor and outdoor virtual environment that represents an actual physical space (i.e. a school campus). In the first aim of the study, we will compare spatial cognitive map development in early and late blind as well as low vision individuals using the HAGA software versus a group learning setting in which participants learn the layout of the campus using a tactile map. The ability to transfer acquired spatial information will then be assessed with navigation tasks carried out in the actual physical environment. In a second aim of the study, we will investigate the neural correlates associated with virtual navigation and prolonged training. Using functional and structural magnetic resonance imaging (fMRI), we will identify and compare the neural networks associated with these skills in early blind and sighted individuals. The innovative combination of an intervention clinical trial study and hypothesis-driven neuroscience investigation will better inform the future design of assistive technology and broad-based O&M training for the blind. From a clinical perspective, this work will have potentially important implications in terms of rehabilitative training by improving navigation skils and promoting independence, while dispelling anecdotal preconceptions regarding the abilities (and disabilities) of the blind and visually impaired.

Project Summary The objective of the proposed research is to better characterize and understand functional vision processing deficits in cerebral/cortical visual impairment (CVI), the leading cause of congenital vision loss in the United States and developed world. Perinatal damage to developing visual pathways and structures leads to impaired visual spatial processing abilities, particularly in the setting of high environmental complexity and attention demands. Standard clinical assessments and traditional psychophysical stimuli fail to characterize these functional vision deficits due to their lack of ecological validity. To address this unmet need, we have developed a novel virtual reality (VR) based testing platform to assess visual spatial processing abilities in tasks that approach real world situations. In this cross-sectional behavioral study, performance in children and adolescents with CVI will be compared to age-matched ocular visual impaired (OVI) individuals as well as neuro-typical developed sighted controls. Using recorded eye tracking metrics, we will characterize visual search performance and the effect of manipulating stimulus factors in the VR environment. Our central hypothesis is that VR based assessment will reveal impairments in visual spatial processing that are not characterized by standard clinical assessments. In our first aim, we will compare visual spatial processing abilities using two VR based visual search tasks. The first is a static object visual search task (the ?virtual toy box?) in which participants must search for a toy positioned in an array of distractor elements (other toys). The second is a dynamic object visual search task (the ?virtual corridor?) in which participants must search for the principal of a school in a crowd of distractor elements (other individuals walking in a school corridor). In both tasks, visual search performance will be assessed by varying the number of surrounding distractor elements. We hypothesize that in contrast to individuals with OVI and sighted controls, CVI participants will show greater impairment in performance as a function of increasing visual task demands associated with environmental complexity. In the second aim, we will characterize the effect of manipulating environmental factors using the VR environment on spatial processing abilities. We hypothesize that compared to baseline performance, individuals with CVI will reveal improved performance when target saliency is enhanced, while manipulations that decrease overall target saliency and/or increase task complexity will be associated with impaired performance. The proposed work is of great significance given the potential for developing a novel and ecologically valid VR based platform that provides for superior assessment of visual functional deficits in individuals based on their type of visual impairment. Furthermore, this investigation will help lay the ground work for the creation of new adaptive tools and strategies designed for an individual's specific developmental and rehabilitative needs. This is of particular significance for individuals with CVI; a population that has been greatly underserved despite its important

Summary The objective of the proposed research is to better understand the underlying neurophysiology of cerebral/cortical visual impairment (CVI), the leading cause of congenital vision loss in the United States and developed world. CVI is associated with peri-natal damage to visual cerebral structures and pathways, and leads to a myriad of impairments in visual function. Despite this alarming public health issue, there is a fundamental gap in our understanding as to how the visual system develops in the setting of cerebral compared to ocular based visual impairment. Current studies using standard clinical imaging modalities are limited in their ability to characterize brain functional reorganization in the setting of widespread neurological injury. To further advance our understanding, we will employ multi-modal neuroimaging to characterize whole brain as well as regional structural and functional brain connectivity in CVI associated with periventricular leukomalacia (PVL). In our first aim, we will characterize white matter integrity and structural connectivity using high angular resolution diffusion imaging (HARDI). In our second aim, we will characterize functional brain connectivity networks using resting state functional connectivity (rsfc)MRI. Using a graph theoretical analysis framework, we will then investigate network topological properties and the coupling between structural and functional networks. Further characterization of functional connectivity will be carried out using stepwise functional connectivity (SFC) analysis. This complementary approach allows for the investigation of widespread network alterations on information transfer across the entire brain, and represents a key distinguishing innovation of this proposal. Specifically, the examination of topological characteristics and the nature of structural-functional network coupling will lead to a better understanding of CVI by uncovering the nature of network alterations in the setting of congenital brain injury and how it relates to visual function. Findings will be compared to ocular visually impaired (OVI) individuals (matched for residual visual function) as well as neurotypical sighted controls. Our overarching hypothesis is that CVI is associated with key differences in the organization and relationship between structural-functional connectivity networks. Furthermore, we predict that in CVI, functional networks responsible for visual processing will show evidence of reorganization in response to large-scale white matter injury, and this may serve as a useful biomarker in relation to clinical functional assessments. This study will provide a high level of insight that has not been previously achieved by previous investigations relying on standard clinical imaging approaches. Uncovering how the brain develops in the case of CVI and how it differs from ocular based visual impairment is a crucial first step in developing a neurorehabilitative framework specifically designed for the care of children with this condition. This is of great significance for individuals with CVI; a population that has been immensely underserved despite its important

Summary Cerebral (cortical) visual impairment (CVI) is the leading cause of congenital vision impairment in the United States. Yet, there remains an alarming gap in our understanding as to how observed visual perceptual deficits in these individuals relate to perinatal damage and early maldevelopment of central visual pathways and structures. Children and adolescents with CVI show striking impairments in complex motion processing (a dorsal stream function), particularly in the setting of complex dynamic environmental scenes. While impaired motion perception is an important marker of developmental vulnerability (referred to as the dorsal stream dysfunction hypothesis), standard ophthalmic clinical assessments fail to capture and fully characterize these visual deficits. Thus, in the absence of any apparent ocular abnormality, clinicians may dismiss reported perceptual difficulties, and many individuals with CVI will remain undiagnosed and never receive the timely education and rehabilitative support they need. The objective of the proposed research is to investigate the underlying neurophysiology associated with motion processing deficits in CVI. We will carry out psychophysical behavioral testing combined with multimodal neuroimaging (to characterize structural and functional connectivity along with brain network activation) in children and adolescents with CVI associated with periventricular leukomalacia (PVL). Indices of behavioral performance and neuroimaging outcomes will be compared to neurotypical controls. Our overarching hypothesis is that motion processing deficits will be associated with the maldevelopment of key visual processing pathways. However, altered patterns of functional connectivity and activation of brain networks implicated in complex motion perception may serve as indicators of compensatory neuroplasticity. In our first aim, we will assess motion processing abilities using random dot kinematograms, virtual reality simulations, and visual search tasks. In our second aim, we will characterize the integrity and topology of structural and functional connectivity networks (using high angular resolution diffusion imaging and resting state fMRI respectively) implicated with visual motion and attention processing. The third aim will investigate brain network activation (using functional MRI) in response to our behavioral task assessments. Executed by a multidisciplinary research team with strong community involvement, this combined behavioral assessment and multimodal imaging approach represents a key distinguishing innovation of the proposal. This study will provide convergent and high-level insights into the neurophysiological basis of visual motion perceptual deficits in CVI. The proposed program of research is highly significant given that uncovering brain-behavioral associations in the case of CVI represents a crucial step in establishing a neurorehabilitative framework specifically designed for the care of these children; a population that has been greatly underserved despite its important