Andreas Keil - US grants

DESCRIPTION (provided by applicant): Social phobia has been related to dysfunctions of attention allocation that include hyper-vigilance and subsequent perceptual avoidance of social threat cues. This hypothesized deficit has been difficult to test using behavioral and/or neurophysiological measures because continuous, near real-time measures of resource deployment were not available so far, and the covert processes of attention orienting can not be measured by means of behavioral approaches. The research proposed here directly addresses this difficulty, examining the time course of attentional resource allocation by means of steady-state visual evoked potentials (ssVEPs), evoked by flickering visual stimuli. This electroencephalographic (EEG) measure uniquely provides for a near real-time assessment of visual selective attention. The overall goal of the proposed research is to identify the role of dysfunctional attention to social threat cues in the psychopathology of social phobia. It is planned to determine whether individuals characterized by high social fear or by social phobia direct perceptual and attentional resources towards or away from social threat stimuli, and in what temporal order they do so. Combining the ssVEP approach with self-report, behavioral, and physiological measures, we first aim to quantify the relationship between attention dynamics and the intensity of then aim to study the relationship between dysfunctional attention dynamics and the severity of social phobia during social threat cue processing. Finally, we plan to assess the predictive value of ssVEP-based attention dynamics as prognostic assessment attention. This information has strong implications for improving treatment selection and outcome prognosis. Specifically, matching patients to exposure-based or cognitive treatments will benefit from information as to the nature of their hypervigilance vis-[unreadable]-vis avoidance of social threat cues. PUBLIC HEALTH RELEVANCE: Social phobia has been related to dysfunctions of attention allocation that may include chronic hyper-vigilance and subsequent perceptual avoidance of social threat cues. The research proposed here directly addresses the neurobehavioral mechanisms of such a deficit. It examines the time course of attentional resource allocation in relation to symptom severity of social phobia, and as a predictor of treatment outcome. This information has implications for improving treatment selection and outcome prognosis. Specifically, matching patients to exposure-based or cognitive treatments will benefit from information as to the nature of their hypervigilance vis-[unreadable]-vis avoidance of social threat cues.

A key hurdle in studies of brain function is to be able to measure not only what signals are correlated with one another, but also how they are causally related. Correlation quantifies linear dependence, while causality is capable of distinguishing which brain area is leading the correlated counterparts; causality puts an arrow into correlation. Causality is a difficult problem in data analysis and here a novel measure of conditional statistical dependence to evaluate causality is proposed. The ultimate practical goal is to elucidate the principles of cognitive processing and provide online cognitive feedback to human subjects performing complex tasks.

The objective of this project is to use a recently developed paradigm for electroencephalogram (EEG) quantification based on periodic visual stimulation to improve the signal to noise ratio of visual stimulation on a pre-determined EEG frequency band (here around 10 Hz). The goal is to develop advanced signal processing techniques based on instantaneous frequency (Hilbert transform) to quantify the instantaneous amplitude of a visual stimulus in 32 channels over the scalp.

A recently developed measure of local statistical dependence in the joint space called correntropy will be utilized to evaluate the dependency among instantaneous amplitude time series collected over the scalp. The maximum value of correntropy is a measure of statistical dependence, which is the first step towards causality. To achieve a causality measure, conditional dependence will be evaluated by extending correntropy to conditional correntropy, first for triplets of variables and them to subspaces of arbitrary dimensions. Correntropy is a nonparametric measure of dependence; hence, the new method will be compared to linear and nonlinear Granger causality methods implemented in reproducing kernel Hilbert spaces.

These algorithms will be tested on data collected from human subjects in a study of affective visual perception. The goal is to study and quantify the re-entry hypothesis of emotional perception -- that re-entrant modulation originating from higher-order cortices is responsible for enhanced activation in the occipital cortex when emotionally arousing stimuli are perceived. The signal processing and statistical methods developed here will provide a way to identify dependent EEG channels and causal relationships amongst them during the presentation of the stimulus, effectively tracing the flow of neural activity from the stimulated visual areas to frontal areas and back to the visual cortex.

DESCRIPTION (provided by applicant): Clinical neuroscience studies have suggested that dysfunctional reactivity of the brain circuits mediating emotion may be a key factor in the etiology and maintenance of many psychiatric disorders. It is also well established that the sensory cortical response to emotional stimuli is an important part of a cascade of events - physiological, cognitive, and behavioral - that define emotional reactivity in humans. For instance, anxiety patients show visual responses that are both biased towards threat cues and lacking discriminative accuracy. Mechanistic knowledge is needed that addresses the question of how such perceptual biases towards threat features are acquired (and unlearned) in the human visual system. This has been difficult because reliable methods to quantify single trials of neural activity are not available at this time. In this multidisciplinary research project, we propose to use novel computational and experimental approaches to fill this gap. We aim to objectively characterize and quantify - on a trial by trial basis - the temporal evolution of neura changes in the human visual system that accompany the acquisition and extinction of conditioned fear. An objective and reliable description of the time course of visual changes during fear learning will assist in ongoing efforts aiming to develop objective diagnostic categories of fear disorders, to understand and quantify effects of treatment, and to develop new forms of attention/perception trainings in the fear and anxiety disorders. PUBLIC HEALTH RELEVANCE: Many psychiatric disorders are characterized by heightened attention and perception of threat-related visual information, and such perceptual biases are also seen in healthy observers facing a threatening visual stimulus. Using novel methods in biomedical engineering and neurophysiology, this multidisciplinary research project examines how healthy observers acquire perceptual biases during classical fear conditioning, and how these biases can be eliminated through extinction learning. Finding reliable and valid quantitative neural parameters of fear learning is important for the objective assessment of brain circuitry underlying anxiety disorders in humans, and it also has the potential of establishing neurofeedback treatments whose aim is to alter the functional neuroanatomy of fear.

DESCRIPTION (provided by applicant): Clinical neuroscience studies have suggested that dysfunctional reactivity of the brain circuits mediating emotion may be a key factor in the etiology and maintenance of many psychiatric disorders. It is also well established that the sensory cortical response to emotional stimuli is an important part of a cascade of events - physiological, cognitive, and behavioral - that define emotional reactivity in humans. For instance, anxiety patients show visual responses that are both biased towards threat cues and lacking discriminative accuracy. Mechanistic knowledge is needed that addresses the question of how such perceptual biases towards threat features are acquired (and unlearned) in the human visual system. This has been difficult because reliable methods to quantify single trials of neural activity are not available at this time. In this multidisciplinary research project, we propose to use novel computational and experimental approaches to fill this gap. We aim to objectively characterize and quantify - on a trial by trial basis - the temporal evolution of neura changes in the human visual system that accompany the acquisition and extinction of conditioned fear. An objective and reliable description of the time course of visual changes during fear learning will assist in ongoing efforts aiming to develop objective diagnostic categories of fear disorders, to understand and quantify effects of treatment, and to develop new forms of attention/perception trainings in the fear and anxiety disorders.

The use of multimedia in STEM education is undergoing a remarkable growth. Such growth has been so rapid that it has far outstripped the abilities of research to keep pace with its application. Project LENS is designed to establish a Science of Learning Collaborative Network (SL-CN) consisting of the Educational Neuroscience Laboratory and Center for the Study of Emotion and Attention at the University of Florida, the Laboratory for Visual Learning at the University of Massachusetts Boston, and the Educational Neuropsychology Laboratory at Washington State University. The network brings together scholars from the following disciplines: STEM Education, Cognitive and Developmental Psychology, Neuroscience, Educational Technology, Computer Science, and Educational Measurement. Experts from the Project LENS network will employ novel methods and neuroimaging technologies to investigate multimedia learning in order to address the gap in knowledge developing in this field.

The purpose of this collaborative network is to capitalize on the strengths of each node leveraging expertise in cognitive neurotechnologies (Electroencephalography, functional Near Infrared Spectroscopy, and eye tracking) to enable a rigorous interdisciplinary research ecosystem. Project LENS will advance fundamental research about learning through integrative neurocognitive conceptual and empirical approaches.

This interdisciplinary team will advance the science of learning in several ways, including: 1) While most existing multimedia learning research focuses on cognitive load and learning without much consideration of individual learner characteristics, these investigators propose a paradigm shift to put the diversity of learners and their individual differences in the center of multimedia learning research; 2) While the few existing studies that use the individual differences paradigm focus primarily on the role of working memory capacity, this project takes a broader approach and study individual differences at a more precise level, exploring the role of such attentional and cognitive variables as visual attention span, inhibitory control etc. 3) The integrative and interdisciplinary research approaches used in this project will reduce educational researchers? reliance on self-reports in the study of attention, cognition and learning and promote the use of relevant cognitive neuroscience frameworks and tools to improve the science of learning; and 4) the accumulated data on individual differences will lay important groundwork for the construction of comprehensive computational models that can be used to personalize and adapt multimedia learning.

In addition to advancing the understanding of designing multimedia learning, the network's webinars, guest presentations, and composite mentorship of graduate students will enhance learning, teaching, and student advisement within and across our network nodes. The project will broaden participation of underrepresented groups by focusing on the diverse community college student population with a wide range of demographic, attentional, and cognitive differences, and by recruiting research assistants from groups that are currently underrepresented in STEM. The purpose of Project LENS is to enhance infrastructure for research and education, which would be accomplished by establishing collaborations and partnerships in the science of learning. Project LENS addresses at least three national initiatives: a) the BRAIN initiative (2014), b) American Graduation Initiative (2015), and c) US House Resolution on Dyslexia (#456, 113th Congress).

Project Summary    Emotional dysfunction is at the core of many psychiatric disorders, in particular fear, anxiety, post-­traumatic,  and mood disorders. Describing the neural mechanisms associated with emotional processing is therefore a  critical issue in mental health care. Previous attempts to define the neurophysiology of human emotions in the  cognitive  neuroscience  laboratory  have  been  hampered  by  the  unavailability  of  conceptual  and  methodological  frameworks  for  studying  complex  emotional  responses  in  context  and  with  conflicting  information present. The proposed research establishes a novel technique for combining electrophysiological  recordings,  high  in  temporal  precision,  with  functional  brain  imaging,  which  is  high  in  spatial  precision.  This  approach, called steady-­state potential frequency-­tagging, achieves stimulus specificity, temporal, and spatial  resolution across the whole brain. It is unique in that it allows researchers to identify distinct brain networks  selectively activated by different elements of a complex visual scene?even when the elements are spatially  overlapping  and  accompanied  by  stimulation  in  other  sensory  modalities.  We  combine  this  innovative  approach with a novel conceptual framework that considers changes in visual perception an active part of an  observer?s  emotional  response,  to  address  the  following  Aims:  (1)  We  characterize  the  large-­scale  brain  dynamics  mediating  the  emotional  response  to  an  element  that  is  embedded  in  a  complex  visual  array.  (2)  We  determine  how  conflicting  appetitive  and  aversive  information,  visual  and  auditory,  affects  these  brain  dynamics.  (3)  Finally,  we  translate  this  novel  method  to  socially  anxious  observers,  testing  mechanistic  hypotheses  regarding  the  interactive  effects  of  trait  anxiety  and  chronic  stress  on  short-­term  reactivity  to  emotional  challenge.  The  long-­term  clinical  implications  of  the  proposed  research  are  manifold:  For  diagnostic assessment and for monitoring treatment efficacy, a quantitative brain-­based marker of emotional  engagement  opens  avenues  for  objectively  evaluating  pre-­  to  post-­treatment  changes  in  appetitive/aversive  neural  reactivity.  It  also  enables  measuring  neural  circuit  function  to  enable  quantitative  measurements  of  specific psychopathology and for identifying treatment targets in a personalized medicine framework. 

Project Summary Emotional dysfunction is at the core of many psychiatric disorders, with epidemiological studies noting the growing prevalence of fear, anxiety, post-traumatic, and mood disorders in the United States. The overall goal of the proposed project is to characterize the neural mechanisms that underlie dysfunctional aversive learning in anxiety disorder patients. The failure to discriminate between threatening and safe contexts is at the core of many psychiatric problems, with overgeneralization proposed as a defining feature of anxiety disorders. In this project, we (1) translate a robust basic science paradigm testing different modes of aversive learning into the clinical arena, and (2) establish a quantitative approach for measuring inter- individual differences in aversive learning. The approach relies on a robust index of aversive learning -- the steady state visual evoked potential (ssVEP) -- which is measured by presenting a visual cue at a specific frequency (e.g., 15 times per second, 15 Hz) that then elicits neural activity at the same driving frequency. When a cue is reliably followed by an aversive event (i.e. CS+), the amplitude of the ssVEP is heightened, compared to the amplitude of the frequency at which a safe cue (i.e. CS-) is presented, providing an exquisite measure of fear learning. The current project assesses generalization learning in anxiety disorder patients, by presenting an aversively conditioned CS+ together with safe cues that vary in similarity to the CS+. Pilot data with healthy participants shows neural sharpening (i.e., good discrimination of CS+) in sensors placed over occipital cortex, and neural generalization (enhanced responses to safe cues most similar to the CS+) over parietal cortex, and the proposed study measures aversive learning in 100 participants (80 anxiety disorder patients and 20 healthy controls). Using the ssVEP (as well as startle and self-reports), aversive sharpening and generalization are computed for each participant and for each dependent measure using the norm (Euclidian distance) of the difference between weights modeling sharpening or generalization functions and each participant's z-transformed means across safe cues that vary in similarity to the CS+, producing a single quantitative index indicating the degree of generalization and sharpening for each measure. The project explores the overarching hypothesis that inter-individual differences in the generalization of aversive learning- - quantitatively elucidated using the ssVEP-- are dimensionally related to key features of psychopathology across diagnostic groups. Taken together, this project will provide key information regarding dysfunction in aversive learning, which plays a role in the etiology and maintenance of anxiety, as well as form the basis for developing a novel technique useful in clinical assessment and post-treatment contexts.

PROJECT SUMMARY Shared book reading has been found to have broad developmental benefits for language, socio-emotional and cognitive development. However, the effects of shared book reading on infant development are not well understood. Although healthcare professionals and educators ask parents to read books to their infants early and often, the book reading experience itself has never been systematically investigated in infancy. This work is guided by two specific aims and is expected to result in a better understanding of the effectiveness of shared book reading as a tool for supporting parent-infant interactions and infant learning across the first year of life. The first aim of the proposed research is to determine the extent to which infant and parent visual attentional coupling during shared book reading predicts later: a) infant selective attention and b) infant and parent neural coupling. The second aim of the proposed work is to determine the extent to which books with individually-named characters (e.g., ?Boris?, ?Fiona?) increases parent-infant joint attention and infant selective attention relative to books with generic labels (e.g., ?Bear?, ?Bear?) or no labels and whether attention differs by age. To address the aims of this project, a cross-sectional sample of 6-, 9-, and 12-month old infants and their parents will come to the laboratory and read a book that includes three distinct character labeling conditions (individual names, generic category labels, no label). During infant-parent shared book reading joint attention will be measured using dual eye-tracking. Infants and parents will then return to the lab the next day and infant selective attention and infant-parent neural synchrony will be measured using EEG frequency tagging while infants and their parent view familiar characters across labeling conditions as well as unfamiliar characters. If the aims of the proposed research are achieved, we will have determined the extent to which parent-infant joint attention prompts subsequent selective processing of book content in 6-, 9-, and 12-month old infants. This study will also be the first to record dual infant and parent high density EEG during an experimental task and use neural synchrony as an outcome measure. The dual eye-tracking and EEG findings will allow for a better understanding of dyadic interactions between infants and parents. Finally, we expect that this investigation will show benefits of early shared book reading for infant development. Our long term goal is to use this data to support the inclusion of early shared book reading in early prevention programs targeting those at risk for poor health outcomes or developmental disabilities.

Project Summary Classical aversive conditioning is a well-established laboratory model for studying acquisition and extinction of defensive responses. In experimental animals, as well as in humans, research to date has been mainly focused on the role of limbic structures (e.g., the amygdala) in these responses. Recent evidence has begun to stress the important contribution by the brain?s sensory and attention control systems in maintaining the neural representations of conditioned responses and in facilitating their extinction. The proposed research breaks new ground by combining novel neuroimaging techniques with advanced computational methods to examine the brain?s visual and attention processes underlying fear acquisition and extinction in humans. Major advances will be made along three specific aims. In Aim 1, we characterize the brain network dynamics of visuocortical threat bias formation, extinction, and recall in a two-day learning paradigm. In Aim 2, we establish and test a computational model of threat bias generalization. In Aim 3, we examine the relation between individual differences in generalization and recall of conditioned visuocortical threat biases and individual differences in heightened autonomic reactivity to conditioned threat, a potential biomarker for assessing the predisposition to developing the disorders of fear and anxiety. It is expected that accomplishing these research aims will address two NIMH strategic priorities: defining the circuitry and brain networks underlying complex behaviors (Objective 1) and identifying and validating new targets for treatment that are derived from the understanding of disease mechanisms (Objective 3). It is further expected that this project will enable a paradigm shift in research on dysfunctional attention to threat from one that focuses primarily on limbic-prefrontal circuits to one that emphasizes the interactions among sensory, attention, executive control and limbic systems.