Laurie Cutting - US grants

? DESCRIPTION (provided by applicant): Poor reading comprehension (RC) has significant public health consequences. About 25-30% of adolescents in the U.S. perform at a Below Basic level, a level that does not promote successful academic achievement; however, successful RC intervention for much of this population has been elusive. The evidence suggests that there are multiple factors contributing to RC failure, but we do not yet have a clear understanding how these factors interact over development to affect RC. First, there is scant neurobiological understanding of listening comprehension and word recognition development (the so called Simple View of RC) as related to RC, even though we have shown neurobiologically the importance of speech and print binding for predicting individual differences in reading. Second, research by us and others increasingly shows that executive function (EF) is related to RC, mostly in older readers, thus providing initial neurobiological links to RC theories that include higher order reasoning (Construction-Integration). Despite these findings, it is currently unknown how the neurocognitive correlates of EF influence RC development. The next 5 years of HD044073 thus proposes to fill these gaps in the literature by using a longitudinal design that follows children from 2nd-5th grades, first probing the foundational question of how the neurobiological correlates of word and comprehension-level processing development, across modalities, predicts 4th/5th grade RC outcome (Aim 1). Then, we focus on the role that EF plays across RC development (Aim 2). Such knowledge may reveal the importance and role of EF in the transition from learning-to-read (word recognition emphasis) to reading-to-learn (RC emphasis). Our multimodal neuroimaging and behavioral measures together enable a unique window into neurocognitive systems across RC development, and have the potential for moving forward RC theoretical models and providing insights into why some continue (or sometimes begin) to struggle to read as they get older. In particular, using neuroimaging to capture changes in language networks, thus mapping of the Simple View into measurable patterns of integration and changing connectivity in the brain, will allow us to move toward causal brain based accounts of the powerful but poorly understood link between spoken and written language. Understanding how these skills integrate neurobiologically over RC development (and the role of EF in guiding integration) may hold some answers about targets for early intervention and prevention, especially for older poor readers who typically have both lower and higher-level deficits. Ultimately, this line of work may guide the development of more tailored treatments at more optimal time points, and provide a clearer understanding of how to identify and treat RC deficits (or risk factors/precursors thereof) prior to 4th grade. In summary, we seek to provide a fine grained study of the neurobiological correlates of RC development to understand more about how the transition between critical reading stages happens. The overarching long range goal is to treat RC failure before it impedes school learning. Such work could have wide-ranging implications and public health importance.

children; comprehension; cognition; language; reading disorder; neuropsychology; language disorders; child psychology; short term memory; functional magnetic resonance imaging; human subject; behavioral /social science research tag; clinical research;

DESCRIPTION (provided by applicant): Reading disability (RD) is a serious, life-long condition that has significant public health consequences for society. Past NIH research has provided a lot of information about reading development and intervention in the early grades (K-3). However, few studies have investigated the nature of children who develop RD in the intermediate grades (4th-5th grade). Estimates of this RD (coined by Leach et al. as Late-Emerging RD, or LERD) suggest that the prevalence of LERD is non-trivial, ranging from 20% to 46% of those identified with RD in late elementary school. Thus, it is likely that LERD is a significant contributing factor to the substantial prevalence of reading failure in 4th and 8th grades (which is about 30%; NAEP, 2007) and suggests an urgent public health need for understanding more about the underlying causes of LERD. Within this context, the goal of the current project is to determine the cognitive and neurobiological profile associated with LERD, and establish how LERD is similar or different than early reading failure (RD-Early, or RD-E). To accomplish this goal, the proposed study is composed of two aims. Specific Aim 1 is to identify concurrent behavioral and neuronal weaknesses in a sample of 5th grade children with LERD. The plan is to capitalize on a unique situation in which a randomly selected longitudinal cohort that is part of a previous study (not originally designed to study LERD) is available to us. We hypothesize that children with LERD will show a distinct cognitive and neurobiological profile compared to RD-E, with particular weaknesses in various aspects of oral language and executive function. Specific Aim 2 of the study is to use the areas of identified weaknesses in the fifth graders to guide the development of a predictive battery of cognitive and neurobiological measures to characterize the behavioral and neurobiological profiles of those at risk for LERD in earlier grades. We hypothesize that oral language deficits and executive function deficits will feature prominently in LERD. We plan to follow this second cohort of children for several years, acquiring behavioral and neurobiological data to better understand the development of LERD. Ultimately, this line of research seeks to change current practice by determining what measures schools should include as early identifiers for those at risk for LERD, as well as develop early intervention programs for those at risk for LERD. In addition, by use of both neurobiological and cognitive measures, we will learn not only specifically about LERD, but also will contribute generally to understanding brain maturation, particularly connectivity, over time. Thus, this research will not only be valuable to understanding LERD, but also will be more generally helpful to understanding child development, as it will serve to provide information about brain maturation and its relationship to cognition in developing children.

TRANSLATIONAL NEUROIMAGING CORE C ABSTRACT Project Summary The Translational Neuroimaging Core services will: (1) provide U54 investigators with facilities and services to support their individual neuroimaging research programs in the area of intellectual and developmental disabilities (IDD); (2) develop novel data acquisition and analysis methods for measuring sensory/perceptual, cognitive, and social/ motivational functioning in those with IDD; (3) utilize repositories of ?big data? at Vanderbilt to develop new tools and discoveries for IDD; (4) facilitate interdisciplinary collaborations among VKC investigators who may or may not have neuroimaging expertise; and (5) ensure that the services provided are timely, of the highest quality, and cost-effective. The Translational Neuroimaging Core C will support U54 users in the above areas for magnetic resonance (MR) neuroimaging as well as psychophysiological measures. The Core?s services can be broadly construed into two different categories: (1) those that are responsive to investigators? needs and (2) those that are generative, and provide new directions in IDD for investigators to leverage. Investigator need-based services provided include assistance in (a) experimental design, including selecting appropriate tasks for functional magnetic resonance imaging (fMRI) or electroencephalogram (EEG)/event-related potentials (ERP), (b) identification of the optimal modalities of MR imaging or EEG/ERP/eye tracking acquisition parameters, (c) implementation of MRI and EEG/ERP data collection with special populations (individuals with various IDDs, especially infants and children), and (d) management and analysis of MRI and EEG/ERP/eye tracking data. The generative and innovative component of the Translational Neuroimaging Core C focuses on key areas that are of particular interest for IDD researchers: design of novel experimental paradigms optimized for IDDs; increasing data quantity and quality; and conducting data analysis on a large scale (e.g., across studies). To this end, the Core will focus on developing robust image processing techniques to handle challenging data (e.g., movement artifacts) and leveraging BioVU resources using ?big data? approaches. While expertise and resources in neuroimaging, advanced computing, and data management tools are available at Vanderbilt University, none are tailored for the special needs of those who study IDDs. The Aims and services in Core C all have the central goal: to facilitate cost-efficient discovery that leads to the prevention and/or amelioration of IDD. Each member of the Core has strong ties to the larger Vanderbilt community, thus enabling seamless linkages between entities at Vanderbilt that are critical for the Core. The Core will serve 17 funded IDD research-related projects, along with the Research Project (PI: Wallace).

Understanding the patterns of communication between brain regions, and how they develop across childhood, is critical for understanding the development of the neural mechanisms that implement complex cognitive operations such as reasoning. Functional connectivity, or correlations in patterns of brain activation (measured via fMRI), is thought to reflect this inter-regional communication. But communication between brain regions ultimately depends on structural connectivity: the white matter tracts that, either directly or indirectly, connect them. This proposal is aimed at resolving two open questions: 1) What are the dynamic relationships between structural and functional connectivity, for the key networks known to be involved in reasoning and other higher cognitive processes, as these develop together across childhood?, and 2) How do these dynamic relationships affect developmental improvements in reasoning ability? The answers that we obtain will provide both fundamental insight into the development of brain connectivity and mechanistic insight into the development of reasoning ability. This knowledge could impact future research both on educational and training programs designed to teach reasoning ability, and on interventions or medical programs designed to correct problems in reasoning.

To address these questions, we will combine fMRI, DTI, and behavioral data from three longitudinal developmental datasets, collected at UC Berkeley, UC Davis, and Vanderbilt University. By combining datasets, we are able to examine longitudinal data from 400 children and young adults between the ages of 6 and 22. Our primary measures of interest include a) intrinsic functional connectivity between specific regions of interest; b) structural connectivity, measured via fractional anisotropy along tracts that connect these regions; and c) reasoning ability, measured via standard cognitive tests. Our main analyses will focus on connectivity within and between two brain networks, the fronto-parietal network and cingulo-opercular network, which are most closely associated with reasoning and other higher cognitive functions. Mixed-model regression analyses will be employed to examine concurrent relationships among structural and functional connectivity in these networks and reasoning ability. Multivariate latent difference score models will be employed to examine lead-lag relationships. The outcome of this research will be a model of interacting structural and functional connectivity development across childhood, and of how the co-development of these two indicators of neural communication relates to developmental improvements in reasoning ability.

Reading proficiently is a critical skill. Nevertheless, about 25-30% of children are poor readers. Thus, the need to understand how individuals read and comprehend text is critical. A widely accepted developmental model of reading, the Simple View, demarcates reading as consisting of lower-level (phonemic decoding, i.e., orthographic-to-phonological conversions) and higher-level (comprehension) skills, with each level associated with different types of reading difficulties (RD). Those with dyslexia (DYS) show lower-level deficits, with poor phonological processing thought to play an important explanatory role in their impaired decoding abilities. Recently, interest has focused on basic learning mechanisms that may underlie DYS, including the role of procedural and declarative learning and memory. Evidence suggests that procedural memory is poor in DYS, but that declarative memory may be intact. In contrast to DYS, children with Specific Reading Comprehension Deficits (S-RCD) read words quickly and accurately, but struggle with the higher-level skill of reading comprehension. Studies of S-RCD indicate poor semantic processing despite adequate phonological processing/decoding, as well as neurobiological anomalies of the medial temporal lobe (a structure associated with declarative memory) while reading low frequency words. These findings suggest that declarative memory may be weak in S-RCD. Our overarching goal is to explore the behavioral and neural correlates of learning in declarative and procedural memory systems through comparison of DYS, S-RCD, and typically developing readers and examination of how these two memory systems relate to decoding and reading comprehension more generally. We hypothesize (Aim 1) that DYS will show weaknesses in procedural but not declarative learning, while S-RCD may show the opposite. These differences will also be reflected in neurobiological alterations in functional patterns underlying each system. We also hypothesize (Aim 2) more broadly that when decoding and reading comprehension are examined on a continuum, behavioral and neural indices of declarative/procedural memory will differentially predict the two reading skills. This line of research represents relatively new and uncharted territory in understanding RD, especially S-RCD, and may in the long run help elucidate better treatments for those with reading difficulty, which is a significant public health concern. Ultimately, our plan is to build on this exploratory project to pursue R01 funding.

PROJECT SUMMARY In 2015, over 30% of 4th graders did not show proficiency in reading and math. Given the importance of these academic skills for success in school and employment, understanding more about the mechanisms underlying academic success/failure is a key public health issue. While early reading and math growth each correlate with distinct cognitive skills (phonological awareness for reading and symbolic magnitude processing for math), they also substantially overlap, as seen by: (1) the comorbidity between reading and math difficulties; (2) overlap in genetic variance for reading and math; and (3) the fact that several similar cognitive processes, including executive functions (EFs), are important cognitive correlates of reading and math. Considerable theoretical and empirical evidence also supports the importance of EF to reading and math. For example, while fMRI tasks elicit skill-specific areas [reading: left occipito-temporal; math: intraparietal sulcus], EF regions also are engaged. Although the predictive relations between EF and intervention response are negligible in in school age children who are struggling academically, early EF (in preschool/Kindergarten) significantly predicts later academic success. However, despite these observed relations, there is little understanding of the neural mechanisms by which EF-academic linkages develop, and how distinct neural networks may relate to response to intervention. While brain networks supporting reading, math, and EF have been investigated separately, their integration has not been studied within a developmental and intervention context. Central to the current proposal, our recent work strongly supports a role for EF brain networks in academics: we find that EF neural networks facilitate connections between skill-specific nodes in the brain. We also find that the way EF brain regions interact with reading regions predicts poor readers? response to reading intervention with 95% accuracy. In the current study, we leverage our team?s expertise in longitudinal multimodal neuroimaging to examine how the neural networks supporting EF and skill-specific regions develop and interact. Specifically, we follow 260 children from Kindergarten through 1st grade, and examine how EF and skill-specific neural network interactions predict general academic growth. Then, we drill down further to examine how EF-skill specific network interactions predict responsiveness to (reading) intervention in poor readers. We hypothesize that the interaction between EF and skill-specific neural networks, not the individual networks themselves, will be highly predictive of: (a) reading and math growth from Kindergarten through 1st grade (Aim 1) and (b) response to reading intervention in 1st grade poor readers (Aim 2). In sum, our proposal aims to elucidate how EF influences early academic growth, specifically whether interactions between networks (vs individual networks) are core driving factors in EF-academic links intervention response. Given the commonality of EF deficits across many developmental disorders, the proposed work has high

The Translational Neuroscience Core will: 1) provide IDDRC investigators with facilities and services to support their individual human neuroimaging and psychophysiological research programs in the area of intellectual and developmental disabilities (IDD); 2) continue to develop trans-species methods for acquiring neuroimaging and psychophysiological measures in humans with IDD and IDD mouse models; 3) utilize repositories of ?big data? at Vanderbilt to develop new tools and discoveries for IDD; 4) facilitate interdisciplinary collaborations among IDDRC investigators who may or may not have neuroimaging expertise; and 5) ensure that the services provided are timely, highest quality, and cost-effective. The Translational Neuroscience Core C will support P50 users in the above areas for magnetic resonance (MR) neuroimaging as well as psychophysiological measures. The Core?s services can be broadly construed into two different categories: (1) those that are responsive to investigators? needs and (2) those that are generative, and provide new directions in IDD for investigators to leverage. Investigator need-based services provided include assistance in (a) experimental design, including selecting appropriate tasks for magnetic resonance imaging (MRI) or electroencephalogram (EEG)/event-related potentials (ERP), (b) identification of the optimal modalities of MR imaging or EEG/ERP/eye tracking acquisition parameters (c) implementation of MRI and EEG/ERP data collection with special populations (individuals with various IDDs, especially infants and children), and (d) management and analysis of MRI and EEG/ERP/eye tracking data. The generative and innovative component of the Translational Neuroscience Core C focuses on key areas that are of particular interest for IDD researchers: design of novel experimental paradigms optimized for IDDs, expanding trans-species imaging capabilities, implementing and augmenting novel data acquisition and analysis methods for measuring neural biomarkers of IDD, developing robust image processing techniques to handle challenging data (e.g., movement artifacts), and providing tools to enable optimal establishment, usage, and analysis of ?big data? repositories such as ImageVU. While expertise and resources in neuroimaging, advanced computing, and data management tools are available at Vanderbilt University, none are tailored for the special needs of those who study IDDs. The Aims and services in Core C all have the central goal: facilitate cost-efficient discovery that leads to the prevention and/or amelioration of IDD. Each member of the Core has strong ties to the larger Vanderbilt community, thus enabling seamless linkages between entities at Vanderbilt that are critical for the Core. The Core will serve 22 funded IDD research-related projects.

PROJECT SUMMARY/ABSTRACT Brain development occurs at a rapid pace prenatally and throughout childhood, impacted by dynamic genetic and environmental influences. Studies using advanced neuroimaging have provided significant insights into brain development but have been limited by small sample size, especially for high-risk populations. Substance- exposed infants are at particularly high risk for adverse outcomes; however, findings are inconsistent, making it difficult to disentangle prenatal exposure effects from other adverse influences. The objectives of our HEALthy Brain and Child Development (HBCD) Prenatal Experiences and Longitudinal Development (PRELUDE) consortium are to characterize typical trajectories of brain development from birth through childhood, measuring the influence of key biologic and environmental factors and their interactions on child social, cognitive, and emotional development. We will assess how children prenatally exposed to opioids and other substances, as well as environmental adversity, differ in those brain trajectories and outcomes. Our consortium consists of six centers (Arkansas Children?s Research Institute, Case Western Reserve University, Cincinnati Children?s Hospital, Children?s National Medical Center, University of North Carolina at Chapel Hill, and Vanderbilt University) which have collaborated previously and have complementary expertise in neuroimaging, neurophysiology, longitudinal clinical research, child development, substance exposure and addiction, ethical/legal issues, and clinical care of high-risk infants/children. The PRELUDE consortium will recruit 680 pregnant women with substance use, 680 at-risk pregnant women without substance use, and 1360 comparison pregnant women representative of the general population to contribute to the overall HBCD study. We will work closely with the other sites, the HBCD Consortium Administrative Core, and the HBCD Data Coordinating Center to develop a comprehensive study protocol and ensure compliance of study workflow and data transfer. Our consortium has an optimized research protocol and 4 specific aims: 1) Employ ethical and evidence-based best practices to enroll and retain a diverse cohort of pregnant women into a longitudinal study of infant/child brain development, oversampling mothers from high-risk backgrounds and those using substances during pregnancy; 2) Engage a comprehensive array of maternal- and child-oriented community stakeholders to identify community concerns and priorities regarding this research, minimize risks, and promote long-term engagement of the recruited child-mother dyads; 3) Collect rich data to examine how maternal health context and broader environmental factors may affect the maternal-fetal dyad and neurodevelopment of children; 4) Capture key developmental windows during which maternal and environmental factors may interact with brain and behavioral development of children. The insights from these data will provide greater understanding of factors affecting early childhood brain development, allowing targeted interventions and improved outcomes for mother-child dyads.