Audra M. Sterling - US grants

DESCRIPTION (provided by applicant): Fragile X syndrome is the leading inherited cause of intellectual disability, with the majority of males (95%) having IQs below 70. Most males with fragile X display autistic-like behaviors, and 25-30% meet the DSM-IV criteria for an autism co-diagnosis. Males with comorbid fragile X and autism are typically reported to have more severe overall impairments in cognition and receptive/expressive language. However, the language phenotype within fragile X only and comorbid fragile X and autism is extremely variable across individuals. Moreover, the impact of autism on the language phenotype of fragile X is not clear. The purpose of the proposed project is to determine if there is a grammatical deficit in FXS and in autism, while examining the consequences of comorbid autism on language in fragile X. Research on language development in developmental disabilities to date has been descriptive in nature, as opposed to theory-driven. There is however, a rich theory-driven line of research on grammatical development in children with language impairments. The extended optional infinitive account (EOI) posits that children with specific language impairment seem to get "stuck" in an optional infinitive stage in which they treat the use of certain grammatical morphemes as optional, despite their obligatory status in the adult grammar. Preliminary evidence suggests that children with fragile X and children with autism may demonstrate a deficit in at least one aspect of grammatical development (i.e., finiteness marking;past tense: he walked) independent of nonverbal IQ. This project will advance preliminary work by examining all finiteness markers (BE/DO), as well as non-finiteness grammatical morphemes (i.e., plural -s, possessive -s, present progressive -ing). This investigation will inform whether boys with fragile X show a grammatical profile similar to SLI, or if their language is characterized by global difficulty with all grammatical morphemes. In addition, the impact of co-morbid autism on grammatical development will be examined by comparing boys with fragile X with and without autism and boys with idiopathic autism. Additionally, the proposed study will examine the most effective method of assessing grammar in boys with FXS and boys with autism. Sixty-three boys between the ages of 9-16 years will participate in this study: boys with FXS only, boys with FXS and autism, and boys with idiopathic autism. Participants will complete standardized tests, a language sample, autism diagnostic measures, and a sentence imitation task. These results will inform the phenotypes of fragile X and autism and provide insights into the nature of variability in language impairments across different etiological conditions. The information from the proposed studies will inform (1) hypotheses regarding neural constraints on language development as well as (2) clinical assessment and intervention procedures. This study lays the groundwork for future studies needed to assess additional aspects of the linguistic system. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health given that it contributes to a program of research focused on significantly improving the communication abilities of children with intellectual disabilities, including fragile X and autism. The proposed project seeks to understand the best method of assessment of language in children with intellectual disabilities, which is relevant to NIDCD's mission to improve the lives of individuals with communication disorders. Additionally, by examining the impact of autism on fragile X, the proposed project will suggest hypotheses about neural constraints on language development, which is relevant to the mission of NIDCD and the NIH as a whole.

PROJECT SUMMARY/ABSTRACT A significant number of individuals with neurodevelopmental disorders demonstrate impairments in expressive language, and these impairments have persistent, lifelong effects on development and adaptive behavior. Two neurodevelopmental disorders particularly impacted by language impairments include autism spectrum disorders (ASD) and fragile X syndrome (FXS). ASD affects 1 in 68 individuals, and while etiology is presently unknown, there is a strong genetic component. Fragile X is the most common inherited form of intellectual disability and has a high comorbidity with ASD. Children with ASD and FXS have impairments in language across a number of different domains, including semantics and grammar; however, we do not fully understand the nature of language impairment in these domains, and in particular the impact of ASD on language in FXS. A key component within this line of work involves the integration of neuroimaging methods with behavioral measures of language, in order to identify the key neural substrates associated with language in these complex disorders, but to date this has not been done in FXS. The training and research in this proposal addresses these significant gaps in the field by combining behavioral and neuroimaging methods to address two specific aims: 1) Compare the structural language profiles in children with FXS, with and without ASD, and children with idiopathic ASD, and 2) Examine the neural substrates in FXS and ASD and their association with behavioral language measures. We will recruit three groups of school-age boys, specifically boys with FXS- only (n = 15); boys with FXS and ASD (n = 15), and boys with idiopathic ASD (n = 15). The proposed project represents an innovative design, combining a careful behavioral phenotype with imaging measures of brain volume, white matter microstructure and functional connectivity. The proposed career development and results from the specific aims will allow the investigator to become an independent scientist, by broadening her training to include neuroimaging methods and analyses and developing a plan to adapt the scanning environment to meet the needs of individuals with neurodevelopmental disorders. The results will inform hypotheses regarding the relationship between language in neurodevelopmental disorders and the corresponding neural substrates. This information will be used to develop future projects to determine the longitudinal course of language development, the impact of ASD on this genetic disorder, and the neuroplasticity of the associated neural substrates impacted in these disorders.

PROJECT SUMMARY/ABSTRACT Language impairments in children have a persistent, lifelong impact on social communication, academic performance, and adaptive behaviors. Two clinical groups particularly impacted by language impairments include developmental language disorder (DLD) and fragile X syndrome (FXS). DLD affects 7-13% of school- age children, and is characterized by pervasive impairments in the grammatical system in the absence of an intellectual disability. Fragile X is the most common inherited form of intellectual disability and males with FXS have significant language impairments. Notably, there is a significant overlap in the language phenotype between DLD and FXS, in terms of grammatical production. This is striking given the difference in general cognitive abilities. Importantly, nothing is known regarding areas of overlap and distinction in grammatical comprehension between the two disorders. Additionally, although these two clinical groups have very different cognitive profiles in terms of IQ, there are overlaps in other aspects of cognition, namely executive function. This is particularly interesting, given evidence of a relationship between executive function and language skills during typical development as well as in children with DLD, however, this work is nonexistent in FXS. Comparative studies between disorders with known (FXS) and unknown (DLD) etiology have the potential to inform both theory and clinical practice. Thus, the proposed study has three specific aims designed to systematically investigate areas of overlap and distinction in terms of language with a focus on grammatical production and comprehension and the association with executive function in children with DLD and FXS in a developmental framework. Through careful investigations we will be able to determine the developmental trajectories of grammatical comprehension and production in addition to EF skills in DLD, FXS, and a language matched group of children with typical development. We will recruit children with DLD (n = 40), children with FXS (n = 40), and children with typical development (n = 60). Children will be matched on clause length to ensure similar language abilities. The proposed study will include a combination of standardized assessments, language samples, experimental tasks, and parent report measures taken at two time points in order to track growth and change during this critical period for grammatical development. The proposed study will yield key information regarding children's comprehension of grammar, change over time, best assessment methods, and critical information on the relationships between executive function and grammatical development. The data collected in this study will be used to inform treatment studies designed to maximize both the effectiveness and efficacy of language learning in DLD and FXS in targeted intervention studies.