John J. Foxe - US grants

DESCRIPTION (provided by applicant): Normal cognitive function requires that humans selectively attend to important or relevant elements of their environment while ignoring irrelevant or distracting information. The alternative, whereby all information in the sensory domain is processed to the level of consciousness, does not allow for normal function and is a core deficit in certain neural disorders such as autism, schizophrenia and attention deficit disorder. While the majority of studies to date have focused on how selective processing itself is affected by attention, the current research proposal concentrates on the neural mechanisms by which selective attentional states are first established in anticipation of attentionally relevant stimuli. That is, when the brain is involved in attentionally demanding tasks, it is of considerable advantage to direct attention to the relevant stimulus to be attended, prior to its arrival and to disengage attention from locations or sensory modalities that may contain potentially confusing information. This proposal is designed to specifically address the processes by which attentionally irrelevant information in the environment is ignored or inhibited during selective attention tasks. Recent studies have shown that selective inhibition of potentially distracting information may be subserved by oscillatory brain rhythms in the 8-14 Hz alpha frequency-band. By using trial-by-trial cueing to direct subjects' attention selectively between competing information channels and assessing the brain activity in the intervening period between the rue' and the subsequent imperative stimulus (S2), the brain mechanisms involved in establishing and maintaining selective attentional states are examined. Two convergent methodologies, high-density mapping of event-related potentials (ERPs) and event-related functional magnetic resonance imaging (fMRI) are employed to assess the brain regions that are involved in setting up and maintaining selective attentional states. Spectral analyses are performed to examine the role of alpha-oscillations in this process. The specific aims of this proposal are: 1) to examine the relationship of alpha-inhibitory mechanisms to attentional load and 2) to establish the anatomy of these anticipatory attentional mechanisms using the high spatial resolution of event-related fMRI.

DESCRIPTION (provided by applicant): That the different senses sample unique aspects of physical objects should provide the brain with both a richer description of objects, and converging evidence concerning their position, identity and movement. Although there has been a detailed explication of multi sensory processing in the superior colliculus of cats and a number of multi sensory brain regions have been detailed in non-human primates, we have only a rudimentary understanding of how information from different sensory systems is combined in the human neo-cortex. The purpose of this proposal is to further our understanding of human cortical multi sensory integration through the combined use of event-related potential (ERP) recordings and functional imaging (fMRI). High-density mapping of ERPs recorded from 128 scalp electrodes, co-registration of these maps with individual subject MRI-derived anatomy, and source analysis of the surface recorded data will allow us to assess the brain regions involved in such integrations. Parallel fMRI experiments will allow us to precisely define the brain regions involved in a given multi sensory operation. Integration of ERP source-analyses and fMRI data will provide the spatio-temporal dynamics of multi sensory integration. Critically, the precise temporal resolution of the ERP will allow us to assess the time-course of multi sensory integration effects relative to the time-course of ongoing unisensory processing. We propose to determine: 1) the temporal separation parameters between the unisensory constituents of a bi-sensory audio-visual stimulus that result in modifications of the ERP interactions associated with bi-sensory stimulation, 2) whether spatial separation of bi-sensory stimuli modifies the early ERP interactions associated with bi-sensory stimulation, 3) whether top-down influences (attention) can effect the earliest multi-sensory interactions to bi-sensory stimulation, 4) to assess the effects of simultaneous stimulation in an entirely task-irrelevant sensory modality (vision) upon the ERP interactions with a second task-relevant sensory modality (somesthesis). Specifically, we wish to assess the effects of the irrelevant modality when it either contradicts or confirms task-relevant spatial information, 5) whether illusory changes in the perception of visual apparent motion, which are induced by presentation of simultaneous auditory stimuli, are the result of auditorily driven processing changes in visual motion processing areas. Through these studies, we will begin to explore the neural mechanisms underlying the process of "binding," related inputs across the separate sensory modalities.

The overall goal of this project is to achieve a better understanding of the processes whereby intentions are translated into actions in normally aging adults: so-called 'executive control' processes. Previous behavioral research has suggested significant and progressive reductions in executive abilities in aging adults. The specific aim of this project is to study the executive processes involved in switching from one task to another using high-density electrophysiological recordings (event-related potentials (ERPs)) as our dependent measures. This allows us to directly assess the underlying brain dynamics across the network of areas involved in control processes. Our preliminary data suggest that the deficits in task-switching seen with aging may not in fact be due to prefrontal cortical dysfunction, a commonly held hypothesis, but rather, may result from deficient activation of parietal cortical processes. This has led us to hypothesize that a core deficit in aging may in fact be an inability to sustain attention- a process associated with parietal activations. The experimental paradigm we will use is as follows, and is a modification of a well-established task-switching paradigm, allowing for direct comparisons to the wealth of previous psychophysical data. On every trial, a stimulus comprised of a letter and a number will be presented. For three successive trials, subjects will judge whether the letter is a vowel or a consonant; for the next three trials, they will judge whether the number is even or odd; this sequence will then be repeated. Thus, subjects will be required to switch between a letter-categorization task and a number-categorization task. Their ERPs, as well as their behavioral performance (reaction times [RTs] and error rates), will be recorded. This will allow us to compare subjects' ERPs and behavioral performance on three types of trial: 1) the first trial after subjects have switched from one task to the other ('post-switch' trials); 2) the second trial after a task-switch ('nested' trials); 3) the trial immediately preceding a switch of task ('pre-switch' trials). Thus, the executive processes required to switch will be active before and/or during the 'post-switch' trial. The ERPs associated with these processes will therefore be found a) in the late stages of the 'pre-switch' trials, and/or b) in the very early stages of the 'post-switch' trials. The 'nested' trials provide a baseline against which to compare both the 'pre-switch' and the 'post-switch' trials. The results of these comparisons will shed light on the neural mechanisms underlying the executive processes involved in task switching in both young and normally aging adults. High-density ERP recordings and topographic mapping will permit us to assess the relative contributions of frontal, parietal and earlier sensory areas to these processes.

DESCRIPTION (provided by applicant): Atypical integration of multisensory inputs has been suggested as a major component of autism, with some clinical and behavior-based empirical support for this view. Where and when in the neural processing stream these sensory integration deficits occur is as yet unknown, and gaining an understanding of this will be essential in defining the neuropathology of autism. In fact, there is precious little understanding of the basic development of healthy sensory integration mechanisms in typically developing children, although recent work in animal models is beginning to shed some light. Under this project, we will use established electrophysiological metrics of multisensory integration that we have developed in our laboratory in healthy adults, to test the hypothesis that multisensory integration is impaired in autism. The high-density electrical recordings of neural activity that we record will provide a precise measure of when in the information processing stream sensory integration differs from typically developing matched controls, as well as a good model of the underlying brain processes that are affected. We expect that there are profound developmental effects on how multisensory inputs are treated and we will therefore also characterize the normal developmental trajectory of multisensory integration in typically developing children, using a cross-sectional approach. Specific hypotheses about when and where multisensory processes will be affected in autism are made based on the thesis that there is impoverished connectivity between distant cortical regions in this population, and our predictions are predicated on a rudimentary three-stage model of multisensory integration that we have developed in light of the extant literature. The data acquired under this project will provide a strong empirical test of deficits in multisensory integration processes in autism. Understanding how multisensory integration develops and changes over childhood will significantly inform models of multisensory integration, and provide an initial benchmark against which predictions about possible disordered multisensory integration in a host of developmental disorders can be made.

DESCRIPTION (provided by applicant): The loss of acquired language and motor skills are two main diagnostic criteria for Rett Syndrome (RTT), a devastating developmental disorder caused by known mutations in the MECP2 gene. RTT is characterized by apparently normal development until 6 to 18 months of age followed by a ruinous regression phase that robs RTT children of their ability to speak, as well as leading to major motor dysfunction, breathing irregularities, digestive problems, gait abnormalities and other symptoms. While the genetic basis of the syndrome is understood, much less is known about the cortical alterations associated with it and what skills and abilities may yet be preserved. From clinical observations, we and others contend that these mostly non-verbal children have much greater abilities to understand speech than might at first be apparent. But anecdotal evidence and behavioral assays are inadequate for assessing potentially preserved speech-language function and there is a clear need to bring modern neurophysiological techniques to bear on this issue. In this project, high-density electrophysiological recordings allied with novel systems-identification data-analytic approaches will allow for a direct assessment of the extent of preserved speech reception abilities in RTT. The overarching goal of this project is to develop a thorough neurophysiological quantification of receptive auditory speech capabilities in RTT to deepen our understanding of this disorder. The proposed methods are likely the only feasible way to obtain functional brain measures in RTT, since magnetic resonance imaging has only been obtained under sedation in these children. The project takes a systematic approach to assaying speech-reception, moving from measures of basic phonemic processing, to measures of semantic processing, and in turn to measures that assay the processing of the highly dynamic speech envelope itself during natural speaking conditions. In this way, we can assess the fundamental building blocks of speech processing. The second major clinical symptom of RTT, loss of motor abilities affecting hands, arms, and legs, will also be examined using a novel electrophysiological approach. The processing of semantic auditory information involving action words that involve body parts (e.g. leg and kick) elicits activity in the corresponding parts o motor cortex. If motor impairments in RTT are primarily due to motor cortex dysfunction, then semantic processing for action words should be impaired relative to non-action words. As such, this paradigm represents a potentially powerful functional examination of motor cortical function in RTT. Taken together, the proposed project will examine two fundamental aspects of RTT in a quantitative way using a combination of well-established and cutting-edge methodologies. The derived knowledge could greatly impact ongoing development of assistive technologies to support more effective communication by these individuals with their caregivers and environment. In addition, a thorough quantitative description of two main symptoms of the disorder should lead to an enhancement in determining phenotype-genotype relations as well as an outcome measure for pharmacological clinical trials.

The brain's sensory systems are continually bombarded by a flurry of environmental information, such as shapes, colors, textures, sounds, and smells. In fact, there is far more information than the brain can process simultaneously. As a result, there is an ongoing competition for the brain's limited processing resources. With funding from the National Science Foundation, Dr. John Foxe and his research team are investigating the link between oscillatory signatures of selective attention in electroencephalography (EEG) recordings and the microstructure of long-range connections between brain networks that have been previously implicated in spatial selective mechanisms. The most frequently investigated mechanism of selective attention is spatial selection, where one location in the environment receives preferred processing relative to other locations. An observable signature of spatial selection is increased oscillatory amplitude of brain electrical activity within a particular frequency band, alpha (approximately 10 Hz), over brain regions that process task-irrelevant locations. These oscillations can be imagined as a sine wave, with the peaks and troughs of the sine wave representing relative increases and decreases in neural excitability. Using experimental tasks in which participants are cued to attend to one region of space, while simultaneously ignoring distracting stimuli in other regions of space, Dr. Foxe is EEG measures and structural measure of the brain's long-range connections obtained using diffusion tensor imaging (DTI). Dr. Foxe is leveraging the wide variability across individuals in both oscillatory indices of spatial selection as well as the microstructure of neuronal circuits connecting far-flung brain networks. The coordination of these two neuroimaging techniques (EEG and DTI), as well as the use and exploration of individual differences in brain oscillations and structure, represent novel approaches to the study of selective attention. This work aims to help us understand the relevance of neural oscillations in sensory selection and guide the further development of hypotheses regarding the neural mechanisms employed by networks of selective attention.

Dr. Foxe's laboratory has a long record of translational research. The results of the present studies will provide foundational understanding from which to launch investigations into impairments of attentional selection within clinical populations. Selective attention is disordered in several clinical populations, including individuals with spatial neglect after stroke, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and schizophrenia. In addition, the researchers' use of multiple methodologies (EEG and DTI) will provide an excellent training opportunity for graduate students and postdoctoral fellows. An expertise in multiple methodological approaches, each with their unique strengths and weaknesses, is becoming more and more important for a successful career in the neurosciences. A thorough understanding of the increasingly complex questions being addressed in the neurosciences requires converging findings from more than one experimental tradition. Comprehensive training in imaging techniques in humans will thus provide a terrific base from which to build a successful research career.

DESCRIPTION (provided by applicant): Adolescence is a critical neurodevelopmental period associated with dramatic increases in rates of substance use. Identifying the pathways to substance use and its effects on child and adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain functioning and behavioral, health, and psychological outcomes. This Research Project Site application from the University of California, San Diego and Laureate Institute for Brain Research is in response to RFA-DA-15-015 as part of the ABCD-USA Consortium (5/13), to prospectively determine the neurodevelopmental and behavioral predictors and consequences of substance use on children and adolescents. A representative community sample of 1086 9-10 year olds enriched for high- risk characteristics will be recruited, contributing to the sample of 11,111 to be collected from 11 hubs across the ABCD- USA Consortium. All participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, mobile monitoring and careful assessment of substance use, environment, psychopathological symptoms, and social functioning every 2 years. Interim annual interviews and quarterly web-based assessments will provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. These Consortium-wide data obtained during the course of this project will elucidate: 1) the effects of substance use patterns on the adolescent brain; 2) the effects of substance use on behavioral and health outcomes; 3) the bidirectional relationship between psychopathology and substance use patterns; 4) the effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) the gateway interactions between use of different substances. This hub's Research Project focuses on mechanisms of substance use disorder, special populations with high use prevalence, and the use of drugs other than marijuana. (1) We will determine whether individual differences in neural processing of antireward (i.e., negative reinforcement mechanisms) in amygdala, insula, and anterior cingulate are associated with increased negative emotionality and pain, predict initiation of use and problem use, and are in turn further dysregulated by substance use. (2) We will determine whether protective environment factors and ethnic identification in minority youth are linked to healthier antireward processing and better substance use outcomes. (3) We will determine whether antireward neural processing predicts increased use of illicit drugs other than MJ including misuse of prescription drugs, if such use predicts subsequent exaggerated antireward processing, and if gateway interactions exist between substances. Finally, we will use machine learning approaches to develop a youth-specific risk calculator that will enable us to identify individually- based modifiable risk factor, providing brain-based targets of future novel prevention and intervention approaches.

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA-DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child?s changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.

Project Summary: The Administrative Core (ADM) of this new University of Rochester (UR) IDDRC application serves as the main coordination hub of a fully integrated system of four scientific cores that support the crucial work of 105 UR-IDDRC investigators currently prosecuting 202 basic, translational and clinical research projects in the domain of IDD research. These cores are: Human Phenotyping & Recruitment (HPR); Translational Neuroimaging & Neurophysiology (TNN); Cell & Molecular Imaging (CMI); and Animal Behavior and Neurophysiology (ABN). The ADM Core brings together two international leaders in the field of IDD research, Professors John Foxe and Jonathan Mink, both with a wealth of complementary leadership experience, to coordinate and prosecute this effort. In consultation with the UR-IDDRC community, they have formulated a clear and progressive mission of excellence in IDD research, one that places the people we serve, those with an IDD, at the heart of our Center, and one that promotes equity, inclusion, diversity, and cultural/linguistic competence. The ADM leadership has identified five thematic research clusters that serve to coalesce our portfolio into a coherent well-articulated IDD program, and around which we will build our future. These are: (1) Rare & Orphaned Diseases of Neurodevelopment; (2) Parental Stress & Early Life Exposure as Determinants of Brain Development; (3) Neuroinflammatory Mechanisms in Pathological Brain Development; (4) Autism Spectrum Disorder; and (5) Multisensory & Sensorimotor Integration. The ADM coordinates a substantial pilot grant program, supported through extensive philanthropic efforts and substantial University support, distributing $400,000 per annum in a highly competitive program designed to promote high-risk high- return IDD projects. We have set in place an innovative system of educational activities for pre- and post- doctoral trainees, and a substantial dissemination effort that includes multiple online social media outlets (with closed captioning in Spanish, and ASL translators at live events), an effort that has been specifically designed to be consumable by the public. The ADM coordinates a major data archiving and sharing effort across the Cores, interfacing with the UR CTSI and leveraging our state-of-the-art Bio-Lab Informatics System (BLIS). The Core has established reportage and systematic assessments that continuously scrutinize and evaluate the functioning of the center, ensuring that efficiency and cost-effectiveness are maintained at the highest levels and that the Cores evolve to be fully responsive to changes in technology and systems. The ADM is supported by five key advisory committees that provide crucial input regarding ongoing functioning of the center. These are: (a) The Executive Committee; (b) The External Advisory Board; (c) The Parent and Community Advisory Board; (d) The Internal Advisory Board; and (e) The Core Facilities Management Committee. We stand committed to a clear-eyed purpose, that through our science, we will endeavor each and every day to remove impediments facing people with IDD that prevent them from living the healthiest, most fulfilling lives possible.

The University of Rochester (UR) has a long and extraordinarily rich history of providing first-rate clinical services to persons with Intellectual and Developmental Disabilities (IDD), and in driving new discoveries through research that create increased opportunity for individuals with IDD to live their lives to the fullest of their potential. This proposed UR-IDDRC is founded upon a revolutionary philosophy of medicine, first introduced here at UR Medical Center by Profs. George Engel and Jon Romano in 1977: The Biopsychosocial Model. This simple, yet profound idea, that the person seeking treatment is not merely a product of their biology, but rather, is also an amalgam of their psychology and socio-economic circumstances, places the whole person in all their complexity at the center of medicine. If ever there was a population that deserves to be recognized and treated in this holistic humanistic manner, it is those with an IDD. This UR-IDDRC places persons with IDD at the center of our inclusive neurodiverse mission, and commits to providing excellence in our basic, translational and clinical research, with a singular focus on providing tractable clinical solutions for these individuals. In the pages of this program application, we describe the Center?s crucial scientific infrastructure, which supports four cutting-edge Cores that elevate and accelerate the work of our 105 UR-IDDRC investigators, providing the very latest available technologies and expertise with high efficiency and excellent cost-effectiveness. These Cores are: Human Phenotyping & Recruitment (HPR); Translational Neuroimaging & Neurophysiology (TNN); Cell & Molecular Imaging (CMI); and Animal Behavior and Neurophysiology (ABN). Through vigorous leadership and in close consultation with our UR-IDDRC community and the five key advisory committees that provide counsel to our Administrative Core (ADM), we articulate a set of five research foci that embrace key and established research strengths at our institution while also seeking to expand our program into important areas of concern to the larger IDD community. These are: (1) Rare and orphaned diseases of neurodevelopment; (2) Parental stress and early life exposure as determinants of brain development; (3) Neuroinflammatory mechanisms in pathological brain development; (4) Autism spectrum disorder; (5) Multisensory and sensorimotor integration. Some 202 ongoing IDD projects, and 9 associated training grants, are supported by this infrastructure, and the Center Leadership is committed to further growing this already thriving program by attracting and training new young investigators and clinicians in IDD research. Major efforts to disseminate the work of the Center through media outlets and culturally competent multilingual publications, oriented at our community, are in place. Outreach to our IDD community and the public at large is a central concern of the UR-IDDRC. Leveraging the enormous financial commitment of the University of Rochester?s leadership to developing the UR-IDDRC, and through a philanthropy-driven annual pilot grant fund of $400,000, UR-IDDRC leadership is strongly positioned to prosecute an innovative transformative IDD research agenda over the proposed five-year term of this program.