Reyna L. Gordon, Ph.D. - US grants

? DESCRIPTION (provided by applicant): To understand speech and eventually develop communicative language skills, young children must segment and parse a complex acoustic signal. Recent theoretical accounts propose that rhythmic variations in the speech signal facilitate language acquisition by entraining neural oscillations and directing attention to specifc moments in time, such as phrase boundaries. In particular, our preliminary work shows a strong association between musical rhythm and grammar skills in typically developing children. The proposed R03 extends this work to children with Specific language impairment (SLI, a disorder which affects 7% of young children in the U.S.) to investigate rhythm deficits in this population and determine to what extent rhythm skills in these children are predictive of their language difficulties in grammar and word learning. Thus the long-term goal of this project is to identify individual differences in rhythm sensitivity that predict language acquisition outcomes, by differentiating musical and speech rhythm skills from other known factors in disordered language development, as well as illuminating the neural and cognitive mechanisms by which rhythm deficits may impede language development. This R03 proposal employs an individual differences approach as the first step towards this goal, using an original combination of methodologies drawn from child language development, cognitive neuroscience, and statistical modeling. Aims 1a and 1b of the grant will differentiate the respective contributions of speech rhythm, musical rhythm, and auditory working memory to grammar skills in children that have a wide range of grammatical abilities, in addition to investigating the role of rhythm sensitivity in SLI phenotype. Aim 2 will investigate rhythm sensitivity as a predictor in the ability of children with SLI to segment the speech signal and learn word forms. The impact of this project is a better understanding of how rhythm perception contributes to significant grammar and word learning challenges faced by children with SLI, setting the foundation for future translational research directed toward incorporating rhythm in clinical approaches to SLI. These findings are expected to lay important groundwork for future longitudinal work that will test the utility of rhythm in predicting language outcomes, including the following: response to treatments that implicitly manipulate prosody, a causal influence of rhythm training/rhythm skills on grammatical development and word learning, and utilization of rhythm sensitivity to help discern which late-talking children will resolve from those who will develop SLI.

Gordon K18 Project Summary How does the neurobiological architecture of the human brain give rise to the amazing capacities of learning language and making music? The present proposal aims to map biomarkers of rhythm and grammar traits, two skills that the PI?s preliminary work has shown to share a large proportion of variance. Furthermore, both language and music have a significant amount of heritability. Despite this, a potentially shared genetic basis, especially in the areas of rhythm and grammar, has been virtually unexplored. Rhythm is a form of communication essential not only to music but also to speech: rhythmic cues aid the listener to parse and process the grammatical aspects of sentence structure that are crucial for communicating in the spoken and written modalities. This proposal integrates diverse methodological approaches to characterize the neurobiology of rhythm at multiple levels, exploring the hypothesis that genes expressed during the development and functioning of brain networks that allow humans to perceive rhythms (both in speech and music) lead to individual differences in neural endophenotypes, which in turn influence children?s acquisition of grammatical structures. Aim 1 investigates the contribution of sensitivity to speech rhythms and musical rhythm to spoken grammar phenotypes. Aim 2 investigates shared versus separate genetic and neural architecture of rhythm and grammar phenotypes in children, using a recently developed method for imputing gene expression in brain tissue (PrediXcan). Aim 3 examines the relationship between rhythm biomarkers and the genetic architecture of communication across species. This mentored training award combines methods for behavioral phenotyping of rhythm skills in children (fine-tuned in the PI?s lab) with two cutting-edge genetics approaches (PrediXcan and Gene Set Enrichment Analysis). The innovative inter-disciplinary approach responds directly to the BRAIN Initiative?s call to integrate new technologies and approaches to map neural circuits that vary in resolution, linking activity across spatial scales from genotype to gene expression in brain tissue to behavioral phenotypes, and to discover how neural patterns are transformed into cognition and perception. By providing intensive Human Genetics research training to the PI, a Cognitive Neuroscientist, this K18 mentored training grant also fulfills the mission of the BRAIN Initiative to educate investigators across disciplines and invest in future innovations that can results from large-scale integration of data across fields, in order to address long- standing questions about how our brains allow us to communicate. Moreover, the project also lays groundwork for future pursuit of innovative brain- and genome-based diagnosis and personalized treatment of childhood language disorders (e.g., language impairment, stuttering, and dyslexia) that could potentially benefit from rhythm-based therapeutic approaches.

PROJECT SUMMARY. Specific Language impairment (SLI) is a common, life-long communication disorder characterized by difficulties acquiring grammar and vocabulary that affect children's quality of life, success in school, and livelihood. There is an urgent need to increase identification and treatment of children with SLI. Although SLI is known to be heritable, the underlying neurobiology of the disorder is not yet clear. Recent work by the PI has shown robust associations between rhythm and grammar traits in children, pointing to rhythm resilience as a variable involved in spoken grammar skills. Emerging evidence in the field points to co-morbid rhythm deficits and grammatical deficits in SLI, pointing to weaknesses in rhythm sensitivity as an SLI risk factor. Furthermore, rhythm and grammatical traits are both heritable, and both involve dynamically orienting attention to hierarchical structure over time, but no prior study has directly compared the genetic basis of rhythm and grammar. Here we take an understudied but promising approach to investigating potentially shared genetic architecture to rhythm deficits and SLI. Since sound patterns (across species) used to communicate are organized rhythmically, it is highly likely that present-day speech and language capacities are built on pre- existing genetic architecture for communication, which may include the rhythmic aspect of communication. Children with SLI may thus have heritable rhythm deficits that impair their ability (via common neurobiology) to process the structure of language during grammatical acquisition. The present proposal integrates new methods of genome analysis with rhythm cognition experiments aimed at understanding the mechanisms underlying the potential contribution of rhythm deficits to SLI. Aim 1 harnesses large-sample bio-repositories and extant data with Genome-Wide Association Studies (GWAS) methodology to characterize the genetic architecture of developmental language disorder. This approach allows us to construct the largest sample sizes yet for developing a genetic prediction model for SLI and to investigate the clinical significance of genes involved in SLI. Aim 2 utilizes a GWAS approach in a novel dataset to provide important new knowledge on the genetic basis of rhythm. Armed with novel knowledge about the neurobiological markers of SLI and rhythm deficits, we will then investigate a potential influence of rhythm on grammar-related traits (Aim 3a) and grammar states (Aim 3b), using an innovative selection of genomic analyses and a series of targeted laboratory experiments in children with SLI. By testing this framework of rhythm risk and resilience, these studies lay essential groundwork for multiple future avenues of improving identification and treatment of children with SLI. This project directly responds to NIDCD's call to identify genetic factors and co-occurring conditions that contribute to language impairment and to develop biomarkers of SLI. Moreover, new knowledge of the genetic basis of rhythm may also have relevance for other communication disorders that have co-morbid rhythm deficits (e.g., stuttering, dyslexia).