Mark A. Eckert - US grants

Dyslexia is a form of reading disability that affects a significant proportion of children. Efforts to explain dyslexia have identified neural and chromosomal risk factors for dyslexia and the deficits related to dyslexia. The chromosomal markers implicated in dyslexia include regions related to a variety of developmental abnormalities. A neural risk factor related to dyslexia, Heschl's gyrus duplication, may be one aspect of the phenotypic expression of genes within the regions identified as chromosomal markers for dyslexia. A long term goal of this research will be to perform linkage analysis for Heschl's gyrus duplication. However, a pedigree for Heschl's gyrus duplication must first be developed in order to establish the proper linkage analysis approach. This proposal is designed to collect pedigrees for a Heschl's gyrus duplication and then identify chromosomal markers for the duplication. On a broader level, this proposal will combine two areas of biological research directed towards developing an understanding of the mechanisms that produce dyslexia.

DESCRIPTION (provided by applicant): Biological variation in cerebral asymmetry is associated with behavioral variation in linguistic function. Identifying the relative environmental and genetic contributions to the normal distribution of cerebral asymmetry is a critical step in identifying specific causal factors that facilitate or limit verbal ability. Twins can be studied to determine whether the cerebral asymmetry and verbal ability correlation is attributable to genetic factors, environmental factors, or a combination of these influences. This study will examine the additive genetic, shared and unique environmental contributions to a structurally and functionally related set of brain asymmetries. These brain asymmetries have been associated with oral and written language performance and include: planum temporale asymmetry in Wernicke's area, pars triangularis asymmetry in Broca's area, and cerebellar anterior lobe asymmetry. Central sulcus asymmetry will be studied as a non-language control measure. Monozygotic twins can also be studied to identify variables that produce phenotypic discordance. Preliminary observations suggest that perinatal risk factors affect the degree of neuroanatomical and behavioral similarity in twins. This longitudinal study will also determine if cerebral asymmetry changes with age and whether phenotypic discordance is exaggerated or diminishes with age. Results from this study will guide research designed to elucidate the relation between cerebral asymmetry and verbal ability towards genetic and/or environmental sources, may identify perinatal influences on brain development and behavior, will provide information regarding feasibility of molecular studies of cerebral asymmetry, and provide clinicians, patients and families a greater understanding of the biological origins for cognitive ability.

This project examines the structure and function of neural systems that are hypothesized to contribute to age-related declines in speech recognition. Large age-related differences in speech recognition are observed in complex and demanding listening environments for reasons that are unclear. Aging brains undergo extraordinary changes and there is little understanding of how these changes limit or preserve cognitive abilities. We propose to track the aging of two neural systems that play central roles in hypotheses for declines in speech recognition. Aim 2.1 tests the hypothesis that age-related anatomical declines in brain regions that support speech recognition lead to increased reliance on attention-related frontal cortex for word recognition in normal hearing adults. Aim 2.2 tests the hypothesis that older adults with normal hearing exhibit speech recognition declines when additive anatomical declines within speech-related and attention-related systems limit the ability to attend to degraded speech. Aim 2.3 tests the hypothesis that the most common form of age-related hearing loss, metabolic presbyacusis, leads to compensatory changes within speech-related and attention-related systems. This project uses brain activation experiments to define speech-responsive brain regions where anatomical declines may explain the connection between the aging brain and speech recognition difficulties. This project will provide an understanding of the age-related neurobiological changes that people with normal hearing and with hearing loss experience and thereby provide a foundation for improving the speech recognition of older adults through the development of intervention strategies that are based on the peripheral and central nervous system changes that occur with age.

DESCRIPTION (provided by applicant): The goal of this project is to establish an empirical foundation for measuring locus coeruleus (LC)- norepinephrine (NE) system effects in target networks using functional magnetic resonance imaging (fMRI). LC has been implicated in a variety of mental and degenerative disorders and therefore is an important target for pharmacotherapy. LC-NE neurons have widespread modulatory influences on brain function to regulate attention and modify the gain of sensory neurons, for example. However, it has been difficult to measure such global influences due to limitations in the ability to selectively activae LC-NE neurons while monitoring CNS network activity. It also is unclear how fMRI metrics characterize network effects of phasic and tonic patterns of LC activity that relate to different states of attention. This project seeks to surmount these limitations using innovative optogenetic methods to induce different patterns of activity specifically in LC-NE neurons during ultra high-field functional imaging in vivo. Our preliminary data demonstrate that we can photoactivate LC-NE neurons selectively with optogenetics, and simultaneously observe strong BOLD responses throughout the rat brain. Aim 1 is to fully develop an approach that will measure and distinguish effects of tonic vs phasic LC activation on large scale brain networks with fMRI. Aim 2 is to use fMRI to measure alterations in somatosensory neuronal responses to hindpaw stimulation induced by selective LC- NE activation. These studies will provide the first reliable and valid approaches for evaluating basic science and therapeutic questions about LC function with non-invasive imaging. PUBLIC HEALTH RELEVANCE: The ability to non-invasively measure effects of locus coeruleus (LC) activity on its global target networks using magnetic resonance imaging would advance our understanding of the role(s) for this important brain system in a host of mental functions and dysfunctions, and facilitate rationale development of new pharmacotherapies. This project uses selective optogenetic activation of LC-norepinephrine neurons and ultra high-field functional MRI (fMRI) to provide the first controlled estimates of LC effects on global network function, including during sensory stimulation. The results will establish the extent to which specific patterns of LC activity, resembling those implicated in attention and behavioral flexibility, affect brain networks in ways that can be observed in human subjects using fMRI.

DESCRIPTION (provided by applicant): Methods for retrospective multi-site research will be developed in this project. Integrating data from multiple existing sources has the potential to substantially advance the study of behavior, particularly with respect to understanding complex behavioral disorders. Dyslexia is used as a model to develop methods for complex disorders because of the significant behavioral heterogeneity across people with dyslexia that could be used to develop a richer understanding of reading disability and other complex disorders with equally varied behavioral profiles such as autism or attention deficit hyperactivity disorder. Methods for three critical phases of retrospective multi-site research will be developed. Aim 1 is focused on subject privacy, including the development of an automated data de-identification software tool that can be used for multi-dimensional data sets. Aim 2 is focused on characterizing the behavioral heterogeneity within and across samples of complex disorders, [including the use of multiple imputation to address missing-ness in multi-site data sets.] Aim 3 is focused on how to appropriately analyze data from different samples that have included matched and unmatched case-control study designs. Our goal is to enhance the quality control and scientific power for behavioral and biologic studies of complex disorders, as well as advance the behavioral and neurobiological understanding of dyslexia. By developing standards for integrating behavioral and biological data, retrospective databases could be used to reveal etiologies and establish a consensus for the effective treatment of complex behavioral disorders.

PROJECT SUMMARY/ABSTRACT - OVERALL The overarching goal of the proposed research is to advance our understanding of age-related hearing loss (presbyacusis). More than 37 million American adults have impaired hearing and this number is rising rapidly due to our growing aging society. Interventions for presbyacusis have relatively limited effectiveness, due in part to our incomplete understanding of the distinct metabolic, sensory, and neural mechanisms underlying hearing and communication difficulties in older adults. Four integrated scientific projects are supported by a human subjects core and will test hypotheses about the pathophysiology and genetic, molecular, and cellular mechanisms underlying presbyacusis, examine their consequences for communication, develop tools that improve the diagnostic specificity of presbyacusis, and provide guidance for individualized interventions. Project 1 identifies genetic variants for presbyacusis, characterizes their associated pathophysiology, defines their effects on hearing loss, and assesses the pathologic consequences of these variants in human temporal bones. Project 2 examines how age-dependent changes in the cochlea's innate immune system contribute to degeneration of the cochlear lateral wall and auditory nerve, leading to metabolic and neural presbyacusis. Project 3 uses unique physiologic metrics shared with Project 2 that differentiate metabolic, sensory, and neural presbyacusis in human subjects. Using these same subjects, Project 4 examines acoustic-level phonetic cue and executive system explanations for why older adults experience speech recognition difficulties. Thus, the four scientific projects are interrelated and complementary across levels of analysis to integrate data from animal models, human subjects, and human tissue for the extensive characterization of the pathophysiology of presbyacusis from the inner ear to cortex. Core A (Administration) provides and supports an administrative structure to integrate all scientific activities of the Clinical Research Center. Core B (Human Subjects) recruits human subjects and coordinates their schedules, and supports collection, storage, and analysis of data, which are shared with other research groups to confirm our findings and extend the impact of our research. Together, the proposed research and comprehensive longitudinal human subject database form a cohesive, translational program that will advance our understanding of human presbyacusis and promote scientific progress through sharing of data and presbyacusis phenotyping tools. The Clinical Research Center is unique because of its 30-year longitudinal study of hearing in older adults, clinical and translational approaches, and a focus on providing strong evidence to enhance hearing health care for the millions of Americans who have reduced quality of life because of poorer hearing and communication abilities. The Center will continue to guide the theoretical and clinical study of audition and precision treatments for presbyacusis.

PROJECT SUMMARY/ABSTRACT [The proposed research tests the hypothesis that atypical cerebral symmetries increase the risk for dyslexia through the expression of dyslexia-related genes that are known to regulate brain development.] While there were early promising findings linking planum temporale symmetry to dyslexia, study limitations due to small sample size, inconsistent measurement methods, and varied behavioral and genetic profiles of the subjects produced inconsistent results. [Here we examine planum temporale and other cerebral symmetries associated with dyslexia]. We address the limitations of previous studies by using a large dataset of existing genetic, neuroimaging, and behavioral data, as well as multi-site methods that we developed in the current funding period that make it possible to address dyslexia hypotheses with large multisite datasets. We have demonstrated the ability to deal with missing data, varied image acquisitions, and the behavioral heterogeneity of dyslexia samples that is influenced by sampling approaches. [Specific Aim 1 is to test the hypothesis that atypical cerebral asymmetries are observed for specific reading disability profiles, which are theoretically and empirically-grounded and map to different genetic risks. Specific Aim 2 is to examine the degree to which specific genetic risk variants for dyslexia influence the development of cerebral asymmetries. Specific Aim 3 is to develop the cloud-based infrastructure to provide investigators with secondary data for use in their studies and to replicate our findings (e.g., cerebral asymmetry measures related to dyslexia). The results will provide a consensus on the cerebral asymmetry hypothesis for dyslexia because of our large dataset and collaborative approach, provide behavioral neurogenetic explanations for dyslexia, and provide resources to the research community to advance our understanding of dyslexia and other developmental disorders.]

PROJECT SUMMARY/ABSTRACT ? PROJECT 4 Age-related declines in speech recognition lead to the loss of economic opportunity, social isolation, and depression. These declines are pronounced when listeners must work to recognize speech in noise, particularly older adults with metabolic presbyacusis. Project 4 examines the ability of older adults with metabolic, sensory, and neural presbyacusis to leverage acoustic-level phonetic cues that help identify speech sounds, as well as an adaptive control system that helps to optimize performance during challenging tasks. Aim 4.1 tests the hypothesis that perception of acoustic-level phonetic cues is differentially affected across metabolic, sensory, and neural presbyacusis phenotypes because of differences in the ability to represent critical low-frequency information (e.g., pitch) and brief information with rapid onsets (e.g., voice onset time). Aim 4.2 tests the hypothesis that limited function of a frontal adaptive control system results in unexpectedly poor suprathreshold speech recognition, particularly in older adults with metabolic presbyacusis, because of small vessel disease, a common cause explanation for inner ear and frontal cortical declines. Structural and functional neuroimaging data will be integrated with perceptual decision-making modeling to test these hypotheses and an overarching causal model that declines in auditory and frontal adaptive control systems affect the accumulation of spectral and temporal information and modify decision boundaries during speech recognition. The results from Project 4 are expected to explain why older adults with different mechanisms of presbyacusis experience speech recognition difficulties, which may guide counseling and the design and selection of interventions to enhance communication and quality of life.