Winrich A. Freiwald, Ph.D. - US grants

The contents of our minds are not rigidly determined by the stimuli that happen to be impinging on our senses. Instead, we perceivers actively pick and choose a subset of the available information about the outside world for detailed processing, relegating other information to the shadows of consciousness. This active process of perceptual selection is called attention. With the support of the National Science Foundation, Dr. Winrich Freiwald and his colleagues at The Rockefeller University are tackling fundamental questions about how the brain implements attention. Brain imaging techniques are being used to find the brain areas controlling attention and to find out how they are connected to form attention networks. The research team will test the hypothesis that attention comes about from the interplay of two networks of brain areas, one network controlling what is being paid attention to and the other one scanning the environment for unexpected events currently outside the focus of attention. By their anatomical location in the brain, these networks are referred to as 'dorsal' and 'ventral,' respectively. The researchers are learning how the ventral attention network scans the environment, and how it interrupts processing in the dorsal brain network in order to change the focus of attention. The research uses functional magnetic resonance imaging (fMRI) in humans and monkeys to identify the brain areas and connections of the ventral attention network. Neural activity in relevant brain areas is artificially elicited or suppressed to directly prove how the ventral network affects the dorsal attention network and the overall control of attention.

When a component of the attention system is harmed by a brain injury, severe deficits follow like the attentional neglect of half of the visual environment. Results of the project can lead to new strategies for rehabilitation of brain injuries. Because social stimuli like faces attract attention automatically, the research can also help to understand humans as social beings. With this program, a wide variety of advanced training opportunities in brain imaging techniques for graduate and postgraduate scientists and physicians is offered, and classes are taught on various aspects of vision science. A new laboratory course in sensory neurophysiology is being offered for graduate students. A particular emphasis in this project is placed on introducing high school students and undergraduate students to both results and practice of brain research in order to increase awareness of brain research and interest in scientific practice in general. Because brain imaging of cognitive capabilities like attention quickly captures the imagination of many people, results of these investigations will be disseminated broadly in order to enhance scientific understanding in society. We can control attention voluntarily, yet some external stimuli, 'strange things, moving things, wild animals,' in the words of the psychologist William James, can break through and capture our minds. This project is investigating how the brain allows for such dynamic interactions of attention with the environment. Attention underlies everything we do, whether we just watch the world, walk in it, or think about it. Thus, understanding attention is of fundamental importance to understanding how our minds work.

DESCRIPTION (provided by applicant): Emotions serve essential functions for survival and social communication. Multiple brain areas are recognized as part of the emotional brain, yet how they generate emotions it is currently unknown. The overall objective of this project is to fil this gap in our knowledge and determine how functional interactions between the multiple areas of the emotional brain generate internal states of emotion, what their defining properties are, and how they are expressed in behavior. The approach consists of three components. In Specific Aim 1, activity patterns of the most sophisticated effector of the emotions, the facial expression system, will be monitored with a new recording device, and the statistical properties of these patterns and their transitions will be quantified. The objective of this aim is to objectiely define and automatically detect emotional expressions of the face. In Specific Aim 2, the emotional brain will be harnessed to sensory cues and observable responses using social reflexes, in which seen emotional faces are briefly but reflexively mimicked by their observers. Whole-brain functional magnetic resonance imaging will localize the nodes of the circuit mediating this behavior, and subsequent electrophysiological recordings will identify information flow and transformation through the nodes of this circuit. In Specific Aim 3, the multiple nodes of the emotional brain identified in the literature will be targeted for massively parallel electrophysiological recording to obtain spatiotemporally precise activity profiles from distribute neural circuits during a wide range of behavioral states. These data will be used to infer functional interactions between emotional brain circuits and to determine whether they form discrete or graded activity states, mutually exclusive ones or mixtures, comprising localized or distributed activity. These results will allow for an objective characterization of emotional state and an evaluation of major current theories of the emotions. The outcomes of this project are expected to have major impact on the affective neurosciences, by directly addressing its most fundamental question; motor neuroscience, by revealing the coding principles of the facial expression system; social neuroscience, by deriving the 'vocabulary' of non-verbal communication; and systems neuroscience, by revealing how global distributed activity states interact with local information processing. Disturbances of the emotion and its facial expression are characteristic of many psychiatric disorders including bipolar mood disorders, schizophrenia, or autism spectrum disorders. The project thus meets the strategic objective of the National Institute of Mental Health in pursuing an integrative understanding of a basic brain-behavior process to provide a firm foundation for understanding mental disorders.

This INSPIRE award brings together research areas traditionally supported in the Division of Integrative Organismal Systems in the Directorate for Biological Sciences, in the Division of Chemical, Bioengineering,Environmental, and Transport Systems in the Directorate for Engineering, and in the Division of Behavior and Cognitive Sciences in the Directorate for Social, Behavioral and Economic Sciences. Cognition arises from the activity within complex brain circuits. These brain circuits are laid out according to a species' genetic blueprint. Past and current successes in uncovering the biological basis of cognition include the discovery of areas in the human brain supporting specific cognitive functions, the determination of the roles that specific cell types play in the behavior of animals like the mouse, and the increasingly detailed understanding of the impact specific genes and their alterations can have on cognitive functions in health and disease. The goal of this interdisciplinary project, conducted at The Rockefeller University, is to directly determine the genetic specificity of brain circuit elements that are critically important for high-level cognitive function. This project will be significant by 1) elucidating the complexity of biological organization from the level of genes, through cell types, brain areas, and neural circuits to behavior, 2) developing new technology that will allow researchers to dissect brain circuits underlying cognition with the precision and specificity of model organisms, and 3) improving the understanding of how genetic alterations impact cognition. The interdisciplinary project at the interface of cognitive neuroscience, neural systems, and neurotechnology, is expected to have broader impacts on society by providing insights into some of the deepest questions about the human mind and by offering unique educational and outreach opportunities to improve public understanding of the organization and function of the brain.

The project will investigate the genetic specificity of a multi-node brain circuit that supports cognitive function. The circuit will be localized with functional and structural magnetic brain imaging. Genetic expression patterns of projection neurons within multiple circuit nodes will then be determined using cutting edge molecular techniques. The functions of the projection neurons linking the nodes will then be determined through advanced and custom-designed optogenetic and electrophysiological techniques. The same optogenetic approach will then be used for causal interrogation of projection neurons in cognitive and emotional behaviors. Combining the gene expression and functional data, predictions for how specific polymorphisms in human genes may alter cognitive-emotional abilities will be generated. These predictions will be tested through functional brain imaging and behavioral testing of genotyped subjects. Together, these investigations will provide deep insights into the brain circuits and genetic underpinnings that make possible the cognitive functions of the human mind.

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding of face recognition: why are there multiple neuronal codes for faces in the brain, and how they are transformed through a network of interconnected face-processing areas to support face recognition? Continued existence of this gap constitutes an important problem because of the social importance of faces and because, until it is filled, the neural mechanisms for object recognition remain largely incomprehensible. The long-term goal of the proposed research is to gain a mechanistic understanding of face-recognition in a highly evolved face-processing system similar to that of humans. The overall objective of this particular application is to identiy the rules and mechanisms of informational neuronal transformations between the cortical nodes of the face-processing network. The proposed work will test the central hypothesis that this network is organized as an information-processing hierarchy serving robust face-recognition, in which each processing level performs a face-specific transformation. It takes advantage of the functional organization of the model system that consists of spatially distinct, but interconnected nodes with unique functional specializations - and the fact that these nodes are readily identifiable with brain imaging due to their selectivity for a known visual object category, faces. The rationale of this proposal is that, after completion of this research, we will understand core operations of high-level object recognition at a computational, representational, and mechanistic level. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three specific aims: 1) What visual features do face cells use to represent complex facial information? 2) How do face areas interact to generate high-dimensional facial codes? 3) What is the causal role of face areas for facial coding and face detection? Under the first aim, we will combine single unit electrophysiological recordings in three brain-imaging identified face areas with parametric visual stimulation to reveal the computational mechanisms single cells use to code facial information. Under the second aim, joint electrophysiological recordings from multiple areas will be analyzed to reveal how inter-areal interactions generate face-representations that differ across areas and change over time. Under aim 3, targeted inactivation will be used to reveal the causal role different face processing areas play for informational transformations and for face detection. The proposed research is significant, because it is expected to directly show how an information processing network is organized to transform visual representations of a high-level object category and utilizes them for visual behavior. In doing so it will lift our understanding of visual object recognition to a new level. The research proposed is conceptually and methodologically innovative because it in order to take a systems perspective to the problem of object recognition, tracing transformations of information through a multi-node network and integrating, through a novel combination of methodologies, analyses of single cell mechanisms and population codes with causal interrogation of network function.

This project aims to develop and test a new conceptual framework for understanding brain function, and informing biologically based artificial intelligence systems. The underlying theory holds that the properties of any neuron and any cortical area are not fixed but undergo state changes with changing perceptual task, expectation and attention. Because of the multiple routes by which this top-down information can be conveyed, each neuron is essentially a microcosm of the brain as a whole.

In this framework, a neuron is viewed as an adaptive processor rather than merely a link in a labeled line, taking on functions that are required for performing the current task. The theory accounts for cortical function at the circuit level. Through an interaction between feedback and intrinsic connections neurons select inputs that are relevant to a task and suppress inputs that are irrelevant. The experiments will combine visual psychophysics, fMRI, large scale high density electrode array recordings and optogenetic manipulation. These techniques will be used to measure changes in effective connectivity between cortical areas and the relationship between effective connectivity and the information represented by neurons at different recording sites as animals perform different visual recognition tasks. Computational models will be developed to account for how task-dependent gating of connections can be achieved and will reproduce the functional dynamics observed experimentally. Though the experiments will focus on the visual modality, the findings from the work will formulate a general theory of brain function that is broadly applicable to the brain as a whole.

There is a fundamental gap in our understanding of the computational principles and neural mechanisms by which neural circuits represent complex objects like faces. This conceptual gap constitutes an important problem because, until it is filled, we will not be able to understand face recognition and the reasons for face blindness. The long-term goal is to understand the computational principles and neural mechanisms of face recognition and create a computer face-recognition system based on these principles. The overall objective of this proposal is the determination of the computational principles of local and global face feature coding in the brain's face-processing network. The central hypothesis is that high-level feature tuning in face-selective areas can be understood as the result of the statistical properties of stimulus space and general organizational features of the circuits that process these stimuli. The rationale for this proposal is that completion of the proposed research will provide an understanding, of how neural circuits generate a meaningful representation of complex visual shape, imposing critical constraints on theories of vision. The hypothesis will be tested by pursuing three specific aims, which will determine 1) neural mechanism for facial feature tuning, 2) neural mechanism for categorical face selectivity, and 3) neural mechanisms for transformations of feature tuning. The joint computational and experimental approach will integrate functional magnetic resonance imaging to localize face areas with electrophysiological recordings targeted to these regions and computational analyses of model systems. The approach is innovative through the tight coupling of theoretical principles and experimental validation and by developing novel theoretical and experimental methodologies. The proposed research is significant, because it will unravel principles of neural circuit function that are of general relevance for understanding visual object recognition and multi-node networks. Because the outcome is an advance in understanding circuit mechanisms of social perception, it will identify vulnerabilities of the face-processing system directly relevant to the understanding of face blindness, prosopagnosia, and of altered social perception in syndromes spanning autism spectrum disorders, fragile X, and Williams syndrome.

PROJECT SUMMARY There is a fundamental gap in our understanding of the neural mechanisms of facial movements, both expressive and voluntary ones. The existence of this conceptual gap constitutes an important problem because, until it is filled, we will not be able to explain how the emotions are expressed nor how human speech is controlled, and the processes causing the many disorders of social communication remain elusive. The long-term goal is to understand how facial motor systems, cortical and sub-cortical ones, integrate sensory, emotional, and cognitive inputs and transform them into coherent motor acts. The overall objective of this proposal is the determination of the functional organization and the fundamental mechanisms by which a set of distributed cortical areas controls facial muscles to generate coherent facial movements. The experimental model system is a set of cortical areas with direct projections to the facial nucleus. It allows for testing of the central hypothesis that both emotional and voluntary facial movements are controlled through the coordinated activity of a network of cortical areas, each with a unique functional specialization. The rationale for this proposal is that completion of the research will uncover, for the first time, the neural mechanisms for facial movement control, imposing critical constraints on general motor control theory and the mechanisms and origins of speech. The central hypothesis will be tested through three specific aims: Aim 1 will determine the functional organization of cortex for facial movement control. The working hypothesis that both emotional and voluntary movements are coded by both medial and lateral cortical face-motor areas will be tested using functional magnetic resonance imaging (fMRI) and electrophysiological recordings from fMRI-identified face-motor areas. Aim 2 will determine the functional network structure of cortical face movement areas. The working hypothesis that cortical face-motor areas operate as a network will be tested through functional interaction analyses and joint electrical stimulation and electrophysiology. Aim 3 will determine the principles of descending control of facial musculature. The working hypothesis that facial movements are coded through sequences of neural states, translated by muscle synergies into facial signals will be tested through joint electrical stimulation, electrophysiology and electromyography. The approach is innovative, because it brings a new model system to motor neuroscience, a new paradigm and multi- modal experimental approach to the study of the neural mechanisms, from the level of single cells to large-scale networks, of social communication, and because it challenges long-held views on the neural substrates of facial movement. The proposed research is significant, because it will provide a new dimension to motor control theory, it will define how emotions are translated into expressions and how social signals are generated, it will provide a new model system and foundational knowledge about the neural mechanisms of speech, thus posing important constraints for the understanding of the human condition. Results will improve the understanding and possibly treatment of neurological and psychiatric syndromes of motor function and social communication.

PROJECT SUMMARY The recent discovery of a putative attention control area shows that there is a fundamental gap in our understanding of the neural mechanisms of attentional control. The existence of this conceptual gap constitutes an important problem because, until it is filled, we will not be able to explain a key cognitive function, the flexible selection of information according to current demands and interests, nor to appropriately treat impairments of attention. The long-term goal of this research is to understand how sensory processing and cognitive control mechanisms interact to generate intelligent behavior. The overall objective of this proposal is the determination of the functional organization of the neural circuits supporting attentional control and the mechanisms they are implementing to achieve this function. The experimental model utilizes brain-wide imaging of functional specializations for attention followed by the targeted determination of local neural processes. It allows to test the central hypothesis that there is at least one area in the temporal lobe that is critical for the endogenous control of visual attention. The rationale for this proposal is that completion of the research will re-define endogenous attentional control circuits, which is of direct relevance to neurological practice. The central hypothesis will be tested through four specific aims: Aim1 will determine, using whole-brain functional magnetic resonance imaging (fMRI) and targeted single-unit electrophysiology, the functional specializations of visual attentional control areas and test the working hypothesis that endogenous attention is controlled by specific set of areas sharing a similar organization across species. Aim 2 will determine population codes and dynamics controlling attention and test the working hypothesis that a temporal and a parietal area control the focus of attention in similar ways, yet with differential coupling to its expression into action. Aim 3 will determine the network structure of attentional control areas and test the working hypothesis that the three regions of attentional control are selectively interconnected to form an integrated network of attentional control. Aim 4 will determine the neural mechanisms of visual attentional control over sensory areas and behavior through artificial activation and inactivation during attentive visual processing and test the working hypothesis that a recently discovered temporal lobe area exerts attentional control. The approach is innovative, because it challenges long-held views on the neural circuits of attention and because it introduces a new multi-modal experimental paradigm that promises to shift the approach to neural systems analysis in the cognitive neurosciences. The proposed research is significant, because discovery and characterization of a new attentional control area will fundamentally alter current concepts of attention and brain organization, and because it overcomes a critical barrier in the cognitive neurosciences, the difficulty to bridge between large-scale investigations of functional brain organization with the determination of local neural mechanisms. The project is of direct relevance to neurology and is expected to have a positive impact on the understanding, diagnosis, and treatment of attentional control deficits like hemispatial neglect.

PROJECT SUMMARY There is a fundamental gap in our understanding of how cortical circuit operations aid in high-level visual information-processing like face recognition. The existence of this conceptual gap constitutes an important problem because, until it is filled, it will neither be possible to explain face recognition and the computations face- selective networks implement, nor understand the reasons for face-recognition impairments in disorders like developmental prosopagnosia (face blindness). The long-term goal is to understand the neural mechanisms of face recognition and build an artificial face-recognition system implementing neural computations and thus explain face recognition mechanistically. The overall objective of this proposal presents a major step towards this goal: the establishment of a new approach and a new model system that permits imaging of large neural populations with single-cell resolution and cell-type differentiation within face-selective areas and surrounding regions. These technological advances are expected to lead to the understanding of the functional organization of face areas and how it impacts population codes for faces. The central hypotheses that will be tested, are that face areas are composed of multiple columns with different functional specializations, and that facial codes are highly cell type specific. The rationale for this proposal is that, after completion of the proposed research, the central gap in the understanding of how cortical circuit operations enable high-level vision will have been narrowed through the establishment of a new model system with unprecedented power to uncover the functional organization and circuit mechanisms of population codes of object recognition. The hypothesis will be tested by pursuing two specific aims: 1) Uncover the Spatial Organization of Face-Specializations of the Marmoset Brain; and 2) Determine the Cell-Type Specificity of Face Representations in Face-Selective areas. Two-photon calcium imaging during visual stimulation, combined with tissue clearing and cell type identification through immunohistochemistry will identify the functional organization of face areas and their surroundings with single- cell resolution. The approach is innovative because it presents a new and substantive departure from the status quo and because it addresses an NEI-relevant problem, the neural mechanisms of social perception, in a new way. The proposed research is significant, because it will provide a critical step forward towards a mechanistic understanding of the neural computations performed inside face areas, allow for the development of highly improved artificial face-processing systems, and advance our understanding of the functional organization of face areas in a new dimension and from the level of single cells to the level of face areas. The outcomes will lay the foundation for the determination of the molecular organization of high-level visual circuits and the development of transgenic disease models. The project, therefore, is of direct relevance for the understanding of prosopagnosia, as well as altered social information processing in syndromes like autism spectrum disorders, fragile X, and Williams syndrome.

The autism spectrum disorders (ASDs) are characterized by impairments of social and communicative behavior. The different, yet specific behavioral phenotypes of autism suggest impairments of specific neural circuits of the social brain. Yet, as genetic studies of autism implicate several hundred gene variants, it remains unclear how these genetic variants cause the behavioral phenotypes of autism. Several studies have implicated dysregulation of gene expression in the cerebral cortex in the pathophysiology of ASD. However, they do not address the specificity of cell types involved, how genetic changes alter brain function, or the involvement of functionally specific brain areas. Thus, we do not know whether and how they are altering social brain function selectively or what it is about social brain function that makes it particularly vulnerable in autism. In order to understand autism and its causes, we need to understand how genetic alterations cause the specific changes in the brain circuits that mediate the social and communicative behaviors altered in the condition. The current proposal aims to establish a new approach and a new model system to answer these questions. Using an animal model close to humans, gene expression patterns in functionally defined circuits of the social brain will be characterized. As in human functional magnetic resonance imaging (fMRI) studies, functionally specific regions of the social brain will be localized. This pilot proposal will focus on face-selective brain regions, but the overall approach, once established, will easily translate to other systems. The functional characterizations of the social brain will be complemented by the determination of the connectome of face areas through diffusion-weighted brain imaging. With this knowledge, long-range projection neurons within this functionally defined network will be labeled through a retrograde adeno-associated virus and cell-type specific gene expression patterns will be measured using the Translating Ribosome Affinity Purification (TRAP). The approach will allow for the determination of these expression patterns in glutamatergic cortical projection neurons located in the supra- and infra-granular cortical layers. These are the exact neurons which two recent studies have found to be highly correlated with ASD risk genes. Gene expression patterns of projection neurons will be compared in functionally defined social brain areas to known catalogs of autism-associated gene variations and pathways. The main expected outcome of this study will be the first determination of autism-risk gene expression patterns of functionally identified nodes of the social brain. The rationale of this study is that it will allow us to link autism risk genes to social brain circuits, advance the development of etiological models of autism, and provide crucial information for the generation of transgenic non-human primate autism models. In doing so, critical new links will be forged between the genetic analysis of ASD and functional imaging of brain function in ASD.